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Neuronal Inputs and Outputs of Aging and Longevity

Review ARTICLE

Front. Genet., 02 October 2012 | https://doi.org/10.3389/fgene.2012.00200

Calcium homeostasis in aging neurons

  • Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology – Hellas, Heraklion, Crete, Greece

The nervous system becomes increasingly vulnerable to insults and prone to dysfunction during aging. Age-related decline of neuronal function is manifested by the late onset of many neurodegenerative disorders, as well as by reduced signaling and processing capacity of individual neuron populations. Recent findings indicate that impairment of Ca2+ homeostasis underlies the increased susceptibility of neurons to damage, associated with the aging process. However, the impact of aging on Ca2+ homeostasis in neurons remains largely unknown. Here, we survey the molecular mechanisms that mediate neuronal Ca2+ homeostasis and discuss the impact of aging on their efficacy. To address the question of how aging impinges on Ca2+ homeostasis, we consider potential nodes through which mechanisms regulating Ca2+ levels interface with molecular pathways known to influence the process of aging and senescent decline. Delineation of this crosstalk would facilitate the development of interventions aiming to fortify neurons against age-associated functional deterioration and death by augmenting Ca2+ homeostasis.

Introduction

Fluctuations in intracellular calcium concentration act as signals for a variety of processes in neurons. Most notably, Ca2+ is the major trigger of neurotransmitter release, a process that has been thoroughly investigated over the past decades (Neher and Sakaba, 2008). Moreover, it has also become clear that Ca2+ is essential for a variety of other neuronal functions, including neuronal excitability (Marty and Zimmerberg, 1989), integration of electrical signals (Llinas, 1988; Marty and Zimmerberg, 1989), synaptic plasticity (Malenka et al., 1989), gene expression (Szekely et al., 1990), metabolism (McCormack and Denton, 1990), and programmed cell death (Chalfie and Wolinsky, 1990). Given its central role in processes that are fundamental to the excitable nature of neurons, Ca2+ homeostasis is tightly regulated in these cells (see Table 1 for a summary of the key effectors of Ca2+ homeostasis, in neurons). Here, we briefly overview the main mechanisms neurons use in order to achieve an intricate regulation of the intracellular concentration of Ca2+. In addition, we discuss the accumulating evidence on the potential role of deregulated Ca2+ homeostasis in aging and disease of the nervous system.

TABLE 1
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TABLE 1. Summary of different Ca2+ channels, buffers and sensors, their subcellular localization and function.

Mechanisms of Neuronal Calcium Homeostasis Relevant to Aging and Degeneration

Ca2+ Influx Through the Plasma Membrane

Plasma membrane Ca2+ channels allow the passive influx of calcium ions down their electrochemical gradient. These channels are categorized into two major groups depending on the mechanism controlling their transition between the open and closed conformations: channels gated by voltage (also known as voltage-operated Ca2+ channels, VOCC), and channels gated by ligand binding, in neurons usually L-glutamate (Figure 1; Table 1).

FIGURE 1
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FIGURE 1. Schematic representation of the main Ca2+ homeostatic machinery components in neurons. Individual, key components of calcium homeostatic mechanisms discussed in the text are shown. Arrows indicate direction of ion flux. ER, endoplasmic reticulum; IP3-R, inositol 3-phosphate receptor; NCX, sodium calcium exchanger; NMDA, N-methyl-D-aspartate; PMCA, plasma membrane Ca2+ ATPase; RyR, ryanodine receptor; SERCA, sarco(endo)plasmic reticulum Ca2+ ATPase; SPCA, secretory-pathway Ca2+-ATPase; VOCC, voltage-operated calcium channel.

Voltage-gated Ca2+ channels are multi-protein complexes comprising several different subunits: α1, α2δ, β1-4, and γ (Takahashi and Catterall, 1987; Catterall et al., 1990). The α1 subunit is the largest and it contains the conduction pore, the voltage sensors, and gating apparatus, and most of the known sites of channel regulation by second messengers, drugs, and toxins. The α1 subunits are associated with distinct auxiliary protein subunits (Catterall et al., 1990): the intracellular β subunit, the transmembrane, disulfide-linked α2δ subunit complex, and the γ subunit, a component of skeletal muscle Ca2+ channels also expressed in heart and brain having four transmembrane segments. Although these auxiliary subunits modulate the functional properties of the Ca2+ channel complex, the pharmacological and physiological diversity of Ca2+ channels arises primarily from the existence of multiple α1 subunits. These are encoded by 10 distinct genes in mammals, further divided into three subfamilies based on sequence similarity (Catterall et al., 1990; Snutch and Reiner, 1992; Ertel et al., 2000). Division of Ca2+ channels into these three subfamilies is phylogenetically ancient, as single representatives of each are found in the Caenorhabditis elegans genome. Recently, calcium homeostasis modulator 1 (CALHM1), a glycosylated membrane protein expressed throughout the brain, was identified as the pore-forming subunit of a unique plasma membrane Ca2+-permeable voltage-gated ion channel (Ma et al., 2012).

Based on the characteristics of channel composition, distinct classes of Ca2+ currents have been described (Tsien et al., 1988). In summary, N-type, P/Q-type, and R-type Ca2+ currents are induced upon strong depolarization (Tsien et al., 1991) and are pharmacologically blocked by specific toxins derived from snail and spider venoms (Miljanich and Ramachandran, 1995). N-type and P/Q-type Ca2+ currents are observed primarily in neurons where they initiate neurotransmission at most fast conventional synapses (Catterall et al., 1990; Olivera et al., 1994; Dunlap et al., 1995). More specifically, the CaV2 subfamily members (CaV2.1, CaV2.2, and CaV2.3) conduct P/Q-type, N-type, and R-type Ca2+ currents, respectively (Catterall et al., 1990; Snutch and Reiner, 1992; Olivera et al., 1994; Ertel et al., 2000). Ca2+ entering neurons through the CaV2.1 and CaV2.2 channels is primarily responsible for initiating synaptic transmission at conventional fast synapses (Olivera et al., 1994; Dunlap et al., 1995). CaV2.2 channels are most prevalent at synapses formed by neurons of the peripheral nervous system. In contrast, CaV2.1 channels play a major role at most synapses formed by neurons of the mammalian central nervous system. However, in some central synapses, including a subset of inhibitory interneurons of the hippocampus (Poncer et al., 1997), CaV2.2 channels are predominant in neurotransmitter release.

Ca2+ entry through a voltage-gated Ca2+ channel initiates neurotransmission by triggering vesicular release (Stanley, 1993). Ca2+-triggered synaptic vesicle exocytosis depends on the assembly of the SNARE complex, in which the vesicle-associated v-SNARE protein synaptobrevin (VAMP) interacts with two plasma membrane-associated t-SNARE proteins, SNAP-25 and syntaxin-1 (Sollner et al., 1993; Bajjalieh and Scheller, 1995; Sudhof, 1995,2004). Maturation into a release-ready SNARE complex requires synaptotagmin, an integral Ca2+-binding protein of the synaptic vesicle membrane that provides Ca2+-dependent regulation of the fusion machinery. Ca2+ influx into the presynaptic terminal binds to the Ca2+ sensor, synaptotagmin, and the SNARE complex changes conformation from a trans to a cis state, resulting in the fusion of apposing membranes and the release of neurotransmitter. Neurotransmitter release occurs in two phases: a fast synchronous (phasic) component and a slow asynchronous (tonic) component (Hubbard, 1963; Barrett and Stevens, 1972; Rahamimoff and Yaari, 1973; Goda and Stevens, 1994; Atluri and Regehr, 1998). Both forms of transmission are Ca2+ dependent. Synchronous release driven by the precisely timed presynaptic Ca2+ current results in a large, fast postsynaptic response (Llinas et al., 1981; Sabatini and Regehr, 1996), whereas the slower asynchronous component, resulting from residual Ca2+ remaining in the terminal after an action potential, provides a basal or tonic level of neurotransmitter release at many synapses (Atluri and Regehr, 1998; Lu and Trussell, 2000; Hagler and Goda, 2001).

In addition to voltage-gated channels, a number of Ca2+ channels on the plasma membrane of neurons are activated by the interaction of ligands with their own plasma membrane receptors. The most prominent such ligand in the nervous system is L-glutamate, by far the most widespread excitatory transmitter in the vertebrate central nervous system. L-glutamate activates two general classes of receptors, the “ionotropic” receptors, which are ionic channels, and the G-protein coupled “metabotropic” receptors. Of these, the ionotropic receptors mediate the direct penetration of Ca2+ into the cell. Three forms of ionotropic receptors have been characterized and named after their most widely used agonists. These are the kainate (KA) receptors, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, and the N-methyl-D-aspartate (NMDA) receptors. The channels formed by AMPA and KA receptors are primarily permeable to Na+ and K+ and exhibit a rather low conductance to Ca2+ (Mayer and Westbrook, 1987). By contrast, the NMDA receptors have a considerably higher conductance and are permeable to Na+ and Ca2+ (MacDermott et al., 1986). These receptors do not mediate rapid synaptic transmission, their contribution being primarily to the slow component of excitatory postsynaptic currents. At the resting plasma membrane potential they are powerfully inhibited by Mg2+, whose block is reversed by plasma membrane depolarization (Nowak et al., 1984). Thus, the rapid increase of membrane depolarization following the activation of KA/AMPA receptors by glutamate released into the synaptic cleft reduces the inhibition of NMDA receptors by Mg2+. Therefore, the excitatory postsynaptic potential produced by activation of an NMDA receptor highly increases the concentration of Ca2+ in the cell. The Ca2+ in turn functions as a key second messenger in various signaling pathways. The ability of the NMDA receptor to act as a “coincidence receptor,” requiring the concomitant presence of its ligand and membrane depolarization in order to be activated, explains many aspects of its functional involvement in long-term potentiation (LTP) and synaptic plasticity, a process associated with memory and learning as discussed later.

Efflux of Calcium Through the Plasma Membrane

Two major plasma membrane mechanisms are responsible for the extrusion of Ca2+ from cells (Figure 1; Table 1). One is the ATP-driven plasma membrane Ca2+ pump (PMCA) and the other is the Na+/Ca2+ exchanger (NCX), a complex similar to that discussed later for the removal of Ca2+ from the mitochondrial matrix into the cytoplasm (Baker and Allen, 1984; Carafoli and Longoni, 1987; Blaustein, 1988). Unlike in mitochondria, plasma membrane NCX has the inherent ability to move Ca2+ into or out of the cell depending on the prevailing conditions. When the system is acting to remove Ca2+, energy is supplied by the electrochemical gradient that ultimately results from the activity of the plasma membrane Na+/K+ ATPase (Na+ pump).

Plasma membrane Ca2+ pump has a higher affinity for Ca2+ (Kd = 100 nM) but a very slow turnover, whereas NCX has a much lower affinity (Kd = 1000 nM) but a higher turnover. Both types of transporters are co-expressed in neurons and in astrocytes (DiPolo and Beauge, 1983; Juhaszova et al., 2000). However, the precise role that each plays in removing excess Ca2+ loads under different physiological and pathophysiological conditions remains rather unclear. A major difference is the fact that they exhibit distinct subcellular localization patterns. In particular, some if not all of PMCA found in neurons seems to be localized very close to the neurotransmitter release sites (active zone) of the presynaptic terminals, whereas NCX is excluded from these sites and present in a more dispersed fashion on the rest of the neuron (Juhaszova et al., 2000; Blaustein et al., 2002). Therefore, the PMCA may help keep active zone Ca2+ very low, and function to re-prime the neurotransmitter release mechanism following activity. NCX, on the other hand, is believed to efflux Ca2+ that has diffused away from the active zone and perhaps been temporarily sequestered by the endoplasmic reticulum (ER). Moreover, the discovery of a multitude of PMCA isoforms and alternative splice variants (Strehler and Treiman, 2004; Strehler et al., 2007), as well as recent results on PMCA “knockout” mice and PMCA mutants (Prasad et al., 2007), show that at least some PMCAs play a more specific role in local Ca2+ handling. In addition, a growing number of specific PMCA-interacting proteins have been identified with regulatory, targeting, and signaling functions. These findings support a new paradigm, whereby PMCAs are not only responsible for global Ca2+ homeostasis but are dynamic participants in spatially defined Ca2+ signaling. The main regulator of PMCA function is Ca2+ calmodulin (Ca2+-CaM; Werth et al., 1996). In the absence of CaM, the pumps are autoinhibited by a mechanism that involves the binding of their C-terminal tail to the two major intracellular loops. Activation requires binding of Ca2+-CaM to the C-terminal tail and a conformational change that displaces the autoinhibitory tail from the major catalytic domain. Release of autoinhibition may be facilitated by means other than CaM binding, including by acidic phospholipids, protein kinase A- or C-mediated phosphorylation of specific (Ser/Thr) residues in the C-terminal tail (Werth et al., 1996), partial proteolytic cleavage of the tail (e.g., by calpain or caspases), or dimerization via the C-terminal tail (for a detailed review see Di Leva et al., 2008). Different PMCA isoforms show significant differences in their regulation by kinases and CaM. Interestingly, loss of PMCA function was reported to lead to an increase in the levels of intracellular Ca2+, causing apoptotic death of cerebellar and spinal cord neurons (Kurnellas et al., 2007).

Intracellular Calcium Homeostasis in Neurons

Ca2+homeostasis in the ER

The ER, a complex system of endomembranes, is present in all neurons and extends from the nucleus to the soma, dendrites, and dendritic spines, and down the axon to the presynaptic terminals. Particularly relevant for neuronal function is the ability of the ER to act as a dynamic Ca2+ store, able to actively accumulate Ca2+ and to release it in response to physiological stimulation. As such, the ER contains a variety of channels, buffers, and sensors dedicated to Ca2+ homeostasis (Figure 1; Table 1). In general, Ca2+ exits the ER through several types of Ca2+ release channels, such as inositol 3-phosphate (InsP3) receptors, ryanodine receptors (RyR), nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, and polycystin-2 channels [the relative of transient receptor potential (TRP) proteins]. In neurons, the NAADP receptors were reported to exist in brain microsome preparations (Bak et al., 1999) and Ca2+ release from these channels was described in neurons from the buccal ganglion of aplysia (Chameau et al., 2001), yet their relevance in vertebrate neurons remains unclear. Regarding the TRPs, although they are expressed by neurons, there is so far no evidence for their involvement in Ca2+ homeostasis in these cells. Therefore, in neurons, Ca2+ exit from the ER occurs mainly through the inositol 3-phosphate receptors (IP3-Rs) and the Ca2+ activated RyR, both forming large tetrameric channel proteins. Both receptor families are comprised of multiple members that display distribution patterns that are both temporally and spatially regulated in neurons. For example, there are three RyRs, all of which can be activated by Ca2+ on the cytosolic side with differential sensitivities (RyR1 > RyR2 > RyR3). All three members have been detected in neurons, with distinct patterns that change during development and postnatal growth. For example, postnatally, RyR1 is highly expressed in cerebellar Purkinje cells, RyR3 in the hippocampus, striatum, and diencephalon, while many neurons co-express more than one RyR isoform (Hakamata et al., 1992; Lai et al., 1992; Furuichi et al., 1994; for review also see Berridge, 1998; Hertle and Yeckel, 2007). Regarding their sub-cellular localization, RyRs have been seen in all parts of neurons, including the soma, axons, dendrites, and even the spine apparatus of excitatory neurons. Similarly, there are three InsP3R isoforms with different sensitivities to Ca2+, and further diversity may arise from alternative splicing of InsP3R1. InsP3R1 is the main isoform in neurons in the brain, while InsP3R3 is mainly found in the spinal cord and in glial cells (Berridge, 1998).

Propagating Ca2+ waves is the most dramatic expression of Ca2+ release from the ER, reflecting the Ca2+-induced Ca2+ release (CICR) mode, where elevated cytoplasmic Ca2+ induces further Ca2+ release. Ca2+ waves in neurons were described more recently, after the notion had first been established using Xenopus oocytes (Lechleiter et al., 1991; Parker and Ivorra, 1991). Given the functional compartmentalization of neurons, Ca2+ waves take up different properties depending on their spatial localization and neuronal type diversity. For example, synaptically activated Ca2+ waves preferentially initiate at branch points of dendrites (Nakamura et al., 2002; Larkum et al., 2003; Fitzpatrick et al., 2009) and are mediated by the IP3-Rs (Nakamura et al., 1999). Such waves have been observed in pyramidal neurons of the rodent CA1 and CA3 regions of the hippocampus (Miller et al., 1996; Kapur et al., 2001), in layers 2 and 3 of the cortex (Larkum et al., 2003; Hagenston et al., 2008) and principal neurons of the amygdala (Power and Sah, 2008), all regions heavily involved in memory and learning. Relevant to the cognitive decline and memory loss associated with aging, synaptically induced Ca2+ waves are functionally linked to synaptic plasticity, a process known to require a rise in the postsynaptic concentration of Ca2+. More specifically, there are several cases where synaptically activated Ca2+ release from stores was shown to induce LTP (Yeckel et al., 1999), though it remains controversial as one study challenged this conclusion (Mellor and Nicoll, 2001).

In addition to the channels discussed above, some studies have suggested that presenilin 1 and 2, beyond constituting the proteases in the γ-secretase complex, also function as Ca2+ leak channels in the ER, either by themselves, or indirectly by increasing the activity of IP3-Rs and RyRs (Pack-Chung et al., 2000). In particular, presenilin 2 was shown to interact with sorcin, a cytoplasmic calcium-binding protein that modulates the activity of RyRs (Pack-Chung et al., 2000). Interestingly, in some mutations of presenilin 1 and 2 that are responsible for familial Alzheimer’s disease, disruption of intracellular Ca2+ homeostasis by the ER is the major measurable cellular consequence (Nelson et al., 2010), as discussed later on.

Calcium uptake into the ER lumen results from the function of Ca2+ pumps of the P-type sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) family. This family includes three members (SERCA1–3), as well as two splice isoforms of SERCA2. While SERCA2b is ubiquitously expressed, SERCA2a and SERCA3 are found almost exclusively in cerebellar Purkinje neurons. Inhibition of the SERCA pumps results in a relatively slow emptying of ER Ca2+ stores, with Ca2+ exiting the ER through poorly described pathways (Camello et al., 2002). Ca2+ buffering in the ER lumen is achieved by specific Ca2+-binding proteins. In neurons, the most abundant of these is calreticulin and calsequestrin, while some others such as endoplasmin, BiP/grp78, and proteins of the CREC family also participate in Ca2+ buffering. A main difference of ER Ca2+ buffers is that, unlike their cytosolic counterparts, they have a low affinity for Ca2+ to allow the maintenance of high intra-ER Ca2+ levels.

Ca2+ homeostasis in the Golgi

Ca2+ uptake in the Golgi apparatus involves two groups of Ca2+ pumps: the well characterized SERCAs, discussed above, and a less characterized group of ATPases that were described as secretory-pathway Ca2+-ATPases (SPCAs; Shull, 2000; Figure 1; Table 1). The SPCAs in addition supply the Golgi lumen with Mn2+, which is needed for many enzymatic reactions in this compartment. Mammalian SPCA was originally cloned from rat using a probe derived from sequences of the ATP-binding site of SERCA1 and SERCA2 (Gunteski-Hamblin et al., 1992). The corresponding human gene (ATP2C1) was described by two independent groups (Hu et al., 2000; Sudbrak et al., 2000). Alternative processing of ATP2C1 results in four SPCA1 proteins with C-termini differing in length and specific amino acid sequence (Hu et al., 2000; Sudbrak et al., 2000; Fairclough et al., 2003), SPCA1a, SPCA1b, SPCA1c, and SPCA1d. Ishikawa et al. (1998) later described a second human SPCA isoform, named SPCA2. Its human gene (ATP2C2) was independently described in 2005 by two groups (Vanoevelen et al., 2005; Xiang et al., 2005). The widespread expression pattern of SPCA1 and the observation that homozygous loss of a functional ATP2C1 gene do not seem to be viable suggest that SPCA1 is a housekeeping enzyme. The tissue and cellular expression of SPCA2 appears to be more restricted than that of SPCA1, and based on mRNA data it is expressed in the brain, among other tissues (Vanoevelen et al., 2005; Xiang et al., 2005). It is now well established using a range of different cell types that the endogenous SPCA1 is specifically located in the Golgi compartment (Behne et al., 2003; Van Baelen et al., 2003; Reinhardt et al., 2004; Ramos-Castaneda et al., 2005). The relative contribution of SERCAs and SPCAs to the total uptake of Ca2+ into the Golgi apparatus seems to be cell-type-dependent. The highest dependence on SPCAs occurs in human keratinocytes (Callewaert et al., 2003). This finding is important for explaining the physiopathology of the skin-related Hailey–Hailey disease.

While the potentially specific roles of SPCAs in neurons are poorly understood, our own recent findings (Kourtis et al., 2012) suggest that SPCA1 is both necessary and sufficient in mediating the neuroprotective function of heat preconditioning in a model of heat stroke-induced neurodegeneration. Notably, this mechanism is evolutionarily conserved as it is preserved from C. elegans to mammals. This finding invites the speculation that SPCAs may have a more general neuroprotective role, whose relevance to other forms of neurodegeneration and aging remains to be examined.

Ca2+ homeostasis by mitochondria

Beyond their main role in the cell to produce NADH and ATP, it is now well accepted that mitochondria also function as Ca2+ buffers (Figure 1; Table 1). As proton pumping creates an inside-negative membrane potential in mitochondria, Ca2+ tends to be drawn into the mitochondrial matrix following its electrochemical gradient. This influx is mainly achieved by the mitochondrial Ca2+ uniporter whose conductance is dependent on both intracellular Ca2+ concentration and energy demand. At high cytosolic Ca2+ concentrations and low ATP/ADP ratio more Ca2+ is conducted, whereas at low cytosolic Ca2+ concentration and high ATP/ADP ratio less Ca2+ is conducted. Intricately enough, increasing mitochondrial Ca2+ concentration activates the enzymes of the Krebs cycle, thus causing increased ATP production. As mitochondrial Ca2+ buffering is more energy efficient compared to expelling Ca2+ through the plasma membrane or into the ER, this mechanism is considered of high relevance for neurons in situations when ATP and oxygen demands reach high levels, such as in the case of repeated axon potentials (Contreras et al., 2010).

Calcium is expelled from the mitochondrial matrix into the cytosol mainly by the mitochondrial sodium calcium exchanger (NCX; three Na+ for one Ca2+), in conditions of low ATP demand and oxygen consumption, or through a mitochondrial proton/Ca2+ exchanger (two or more H+ per Ca2+). Indirect experiments with isolated mitochondria under pathological conditions or Ca2+ overload suggest an additional, higher conductance route, through the transient opening of the mitochondrial permeability transition pore (mPTP). However, the physiological relevance of mPTP in Ca2+ homeostasis remains controversial and is not supported by genetic ablation studies (Ichas et al., 1997; Baines et al., 2005). In addition to its contribution in disease, which is discussed later, new roles for mitochondrial Ca2+ homeostasis are also emerging for normal neuron physiology. For example, it was recently described that olfactory sensory neurons require mitochondrial Ca2+ mobilization in order to encode intensity (Fluegge et al., 2012). Therefore, aberrant mitochondrial Ca2+ homeostasis in these neurons converts them into simple signal detectors and impairs their function in olfaction.

Calcium buffers and sensors

A large set of proteins with ability to bind Ca2+ specifically and reversibly provide yet another level of control in Ca2+ homeostasis by acting as sensors or buffers (Figure 1; Table 1). A large family of these Ca2+-binding proteins is the one containing EF-hand Ca2+ binding domains. These motifs consist of two 10–12 residue long alpha helices, oriented perpendicularly against each other, separated by a 12-residue long loop region. EF-hand domains often exist as multiple pairs generating a wide structural and functional variability within this large family of proteins (Kretsinger, 1980). A prominent member of this family, calmodulin, serves as a Ca2+ sensor that translates graded changes of intracellular Ca2+ concentration into a graded signaling response by interacting with various Ca2+-sensitive enzymes.

Another set of EF-hand-containing proteins, represented by calretinin, calbindin, and parvalbumin, function as Ca2+ buffers. These proteins are predominantly expressed by the inhibitory GABAergic interneurons of the central nervous system in specific patterns, therefore contributing to the diversification of these interneurons into distinct subtypes (Van Brederode et al., 1990). A multitude of studies has demonstrated that these proteins modulate the Ca2+ levels locally in the presynaptic active zone or at postsynaptic densities. Moreover, they are thought to actively and differentially participate in modulating neuronal vulnerability to different types of stress. In hippocampal primary cultures, neurons expressing calbindin are less vulnerable to oxidative stress-induced apoptosis because they recover Ca2+ concentration more effectively after stimulation, whereas in cortical neurons this is true for calretinin-containing neurons (Mattson et al., 1991). Similarly, genetic over-expression of parvalbumin in mice rescues motorneurons from injury-induced cell death (Dekkers et al., 2004).

It is generally thought that the transduction of the Ca2+ signal by EF-hand proteins consists a series of conformational changes that occur after Ca2+ has become bound. However, it is important to also mention that there are some exceptions, as no significant conformational changes after Ca2+ binding have been described for at least two of the EF-hand proteins, such as parvalbumin itself and calbindin, which are thus likely to act instead only as temporal Ca2+ buffers. Although most EF-hand proteins reside in the cytosol (and in the nucleoplasm), reticulocalbin is localized in the lumen of the ER (Tachikui et al., 1997). On the other hand, Cab45 (Scherer et al., 1996) and nucleobindin are localized in the Golgi apparatus (Lin et al., 1998) and glycerophosphate dehydrogenase (Pilstrom and Kiessling, 1972) and Aralar are located on the outer face of the inner mitochondrial membrane (del Arco and Satrustegui, 1998; Del Arco et al., 2000).

Another group of Ca2+-binding proteins, collectively known as intracellular neuronal calcium sensors (NCS; Braunewell and Gundelfinger, 1999; Burgoyne and Weiss, 2001), includes five subfamilies: the recoverins and guanylyl cyclase activating proteins (GCAPs), which are primarily expressed in retinal photoreceptor cells and have established roles in the regulation of photo-transduction; the frequenins, visinin-like and Kv-channel-interacting proteins (KChIPs), which are widely expressed in central neurons. One key feature of most NCS is N-terminal acylation: several members of the family are N-terminally myristoylated. Binding of Ca2+ to recoverin, and presumably to other NCS proteins, changes their conformation, exposing the myristoyl residue and hydrophobic portions of the molecule, making them available for membrane (or target protein) interaction. The Ca2+-myristoyl switch could be a mechanism that affects the compartmentation of signaling cascades in neurons and/or the transmission of Ca2+ signals to their membranes (Braunewell and Gundelfinger, 1999; Burgoyne and Weiss, 2001). Although the functions of the last three families are not clearly defined, it has been shown that they interact with multiple target proteins and with nucleic acids as well (Carrion et al., 1999). KChIP3 encodes the protein calsenilin, shown recently to interact with presenilin 1 and 2, two proteins whose mutations result in familial Alzheimer’s disease (AD; Buxbaum et al., 1998; Buxbaum, 2004). Relevant to the neurodegenerative phenotype of AD pathology, this interaction was shown to modulate the proteolytic processing of presenilins. In addition, two other NCS proteins, recoverin and GCAP1 have been involved in degenerative diseases of the retina. Mutations in the GCAP gene have been associated with autosomal dominant cone dystrophy. One of the defects has been related to constitutive activation of guanylyl cyclase that is not properly inactivated by high levels of Ca2+, characteristic of physiological dark conditions, eventually leading to degeneration of cone cells (Dizhoor et al., 1998; Sokal et al., 1998). The other condition [GCAP1(P50L); Sokal et al., 2000] is a milder form of autosomal dominant cone dystrophy in which the mutation reduces the Ca2+-binding ability of GCAP1. Recoverin has been identified as the autoantigen in a degenerative disease of the retina called cancer-associated retinopathy (CAR), in which patients lose vision due to degeneration of photoreceptors (Polans et al., 1991; Polans et al., 1995).

Brain Aging and The “Calcium Hypothesis”

The potential contribution of altered Ca2+ homeostasis at least to some aspects of brain aging and neurodegeneration was first put forward by Khachaturian in the 1980s, with the formulation of the “Ca2+ hypothesis of aging” (Gibson and Peterson, 1987; Disterhoft et al., 1994; Khachaturian, 1994). Early findings in the field that corroborated this hypothesis examined the major transport pathways of Ca2+ during aging and found that at least in some types of neurons, such as the principal cells in the hippocampal CA1 region, there is an increased Ca2+ influx mediated by increased VOCC activity in aged neurons (Landfield and Pitler, 1984; Thibault and Landfield, 1996). Similarly, Ca2+ extrusion through the PMCA was found to be decreased in aged neurons (Michaelis et al., 1996). Subsequently, the focus shifted toward the intracellular mechanisms of Ca2+ homeostasis and their deregulation during aging. Several studies demonstrated that there is an increased release of Ca2+ from the ER stores through both the InsP3 and RyR receptors (Thibault et al., 2007), leading to the proposal that release from the RyR receptor may be a useful biomarker of neuronal aging. Below, we will consider in more detail findings that relate to two key elements of aging: aberrant synaptic plasticity and neurodegeneration.

Role of Calcium in Synaptic Plasticity and Neuronal Excitability During Aging

Aging of the brain is manifested in humans by a progressive cognitive decline associated with weakening of the ability to process new information and of the executive function. The most dramatic effect is notably observed on the function of episodic memory, including spatial memory. The cognitive decline associated with normal aging is not attributed to significant neuronal loss (Gallagher et al., 1996), but is rather thought to result from changes in synaptic connectivity and plasticity. There is a general consensus that memory and learning are molecularly encoded by mechanisms controlling synaptic plasticity in several brain areas. Among these, the afferent pathways of the hippocampus are the most relevant, but other areas such as the amygdale, the visual, somatosensory and prefrontal cortices, and the subiculum also play important roles in processing, integration, and consolidation of new information. Using mainly the hippocampus, numerous studies have deciphered a major role for Ca2+ in the two major forms of synaptic plasticity, LTP (Bliss and Collingridge, 1993) and long-term depression (LTD). LTP represents an increase in synaptic transmission, induced by pattern stimulation of afferent fibers and it is the main process proposed to underlie memory formation. On the other hand, LTD is a means of decreasing synaptic strength, contributing to the loss of synaptic contacts and associated with increased forgetfulness during aging (Foster, 1999,2007; Zhou et al., 2004; Shinoda et al., 2005). Age-related changes in LTP and LTD underline the functional significance of altered synaptic plasticity for cognitive function (Foster and Norris, 1997; Foster, 1999; Foster and Kumar, 2002).

Relevant to the role of Ca2+ deregulation in memory loss, the critical event leading to induction of LTP appears to be the large influx of calcium ions into the postsynaptic spine. Importantly, LTP is blocked by injection of intracellular Ca2+ chelators such as EGTA (Lynch et al., 1983) or BAPTA (Mulkey and Malenka, 1992) and conversely, LTP is induced when the postsynaptic cell is loaded with calcium (Malenka et al., 1988). Therefore, it is well established that a significant elevation of postsynaptic Ca2+ concentration is both necessary and sufficient for the induction of hippocampal LTP (Bliss and Collingridge, 1993). In contrast, a modest rise in Ca2+ concentration results in induction of LTD through activation of protein phosphatases that dephosphorylate AMPA receptors (Artola and Singer, 1993; Lisman, 1989,1994). Due to the differential level of Ca2+ fluctuation involved in the generation of the various forms of synaptic plasticity, the stimulation patterns for the induction of LTP and LTD constitute high- and low-frequency stimulation, respectively.

In general, the effect of aging on synaptic plasticity can be summarized by several key observations: First, the threshold for induction of LTP increases such that higher stimulation frequencies or more induction sessions are required in older animals in order to achieve the same level of potentiation. Second, the threshold for induction of LTD is lowered in aged animals, facilitating its prevalence. Furthermore, the maintenance of LTP is disrupted such that the enhanced transmission decays more rapidly in aged animals. In contrast, LTD and depotentiation, or erasure of LTP, are increased in aged animals due to a lowering of the threshold stimulation needed for induction of synaptic depression (Norris et al., 1996; Foster and Norris, 1997; Kamal et al., 2000; Vouimba et al., 2000). Thus, the age-related decline in synaptic transmission (Barnes, 1994) may reflect a shift in the LTP/LTD balance, with insufficient LTP induction and maintenance and excessive synaptic depression (Foster et al., 2001).

In most of the synapses that support LTP (in the hippocampus and elsewhere), the postsynaptic increase in calcium is mediated through the activation of the NMDA receptor. As already mentioned earlier, NMDA receptor activation allows the influx of calcium only when the receptor is occupied by L-glutamate and concomitantly the postsynaptic membrane is depolarized. Emerging evidence indicates that the synaptic plasticity shift during aging results from changes in the source of Ca2+ such that Ca2+ influx through NMDARs is reduced (Lehohla et al., 2008; Bodhinathan et al., 2010) and Ca2+ influx through L-type VDCCs is increased (Barnes, 1994; Norris et al., 1996; Thibault and Landfield, 1996; Shankar et al., 1998; Potier et al., 2000). The increase could arise from altered gene or protein expression (Herman et al., 1998), or phosphorylation changes of the L-type Ca2+ channels (Norris et al., 2002; Davare and Hell, 2003). Interestingly, the L-type Ca2+ channel blocker nimodipine counteracts age-related learning impairment in rabbits (Deyo et al., 1989; Kowalska and Disterhoft, 1994), rodents (Levere and Walker, 1992), non-human primates (Sandin et al., 1990), and elderly patients with dementia (Ban et al., 1990; Tollefson, 1990).

Additionally, aged neurons show a multitude of defects in Ca2+ homeostasis, including enhanced release of Ca2+ from the ER (Kumar and Foster, 2004; Gant et al., 2006), diminished Ca2+ extrusion through the plasma membrane ATPase (Michaelis et al., 1996; Gao et al., 1998), reduced cellular Ca2+ buffering capacity due to impairment of the SERCA pumps (Murchison and Griffith, 1999), and diminished mitochondrial Ca2+ sink capability (Murchison and Griffith, 1999; Xiong et al., 2002). The overall result is an increase of Ca2+ loads which negatively impact neuronal excitability (Landfield and Pitler, 1984; Khachaturian, 1989; Matthews et al., 2009). Moreover, such an increase in intracellular Ca2+ concentration increases the threshold frequency for induction of LTP (Shankar et al., 1998; Ris and Godaux, 2007), and enhances the susceptibility to induction of LTD (Norris et al., 1996; Kumar and Foster, 2005), ultimately explaining the age-associated deficits in learning and memory. In line with this notion, administration of the cell permeable Ca2+ chelator BAPTA, ameliorates impaired presynaptic cytosolic and mitochondrial Ca2+ dynamics in hippocampal CA1 synapses of old rats (Tonkikh and Carlen, 2009), and enhances spatial learning (Tonkikh et al., 2006).

In the context of LTP induction, a key early finding was the observation that postsynaptic entry of calcium leads to activation of Ca2+/calmodulin complex-dependent kinase II (CaMKII), one of the most abundant proteins in neurons comprising 1–2% of the total protein. Although it is expressed both pre- and postsynaptically, its expression is particularly high in the postsynaptic density, where it is ideally located to respond to changes in calcium concentration. There are more than 30 isoforms of CaMKII and numerous substrates, many of which are located in the postsynaptic density (Fink and Meyer, 2002). CaMKII is generally considered a mediator of primary importance in linking transient calcium signals to neuronal plasticity. Importantly, observations by Silva et al. (1992a),b,(c) indicated that deletion of the CaMKII gene in mice results in impaired LTP and aberrant spatial memory. Moreover, activation of CaMKII is significantly reduced in aged hippocampal neurons (Mullany et al., 1996). The data obtained from studies on rodents have to a large extent, been paralleled by similar findings in other organisms, indicating that several models expressing various forms of synaptic plasticity exhibit a requirement for CaMKII activation. For instance, CaMKII knockout in Drosophila exhibits impaired associative learning, while motor and sensory systems remain unaffected (Joiner and Griffith, 1999). Similarly, knockout of unc-43 (a gene encoding the CaMKII analog in C. elegans) affects the stability of synapses and general neuronal physiology, ultimately culminating in altered function of olfactory neurons (Sagasti et al., 2001).

Beyond activating the CaMKII signaling cascade, Ca2+ also acts as a second messenger that is responsible for the activity-dependent transcription of several key genes (West et al., 2001). The products of these genes are necessary in order to convert the effects of transient stimuli into long-term changes in brain function, a process that is required for the formation of memories. Of the neural-selective activity-dependent genes, brain-derived neurotrophic factor (BDNF) is activated by calcium influx through L-type VOCCs (L-VOCCs) acting on the transcription of BDNF from promoter III (West et al., 2001). BDNF is among the most relevant calcium targets for the modulation of memory. BDNF transcription is up-regulated dramatically by membrane depolarization in vitro (Ghosh et al., 1994; Tao et al., 1998) and by induction of LTP, and associative learning (Ernfors et al., 1991; Patterson et al., 1992; Tokuyama et al., 2000). Moreover, loss of BDNF is associated with impaired LTP among other synaptic defects. It is also well established that BDNF transcription is largely decreased during aging (Tapia-Arancibia et al., 2008), and that epigenetic induction of BDNF transcription in aged subjects significantly ameliorates the cognitive and memory defects associated with aging (Zeng et al., 2011). A summary of the perturbations of Ca2+ homeostasis associated with nervous system aging is shown in Table 2.

TABLE 2
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TABLE 2. Perturbations of Ca2+ homeostasis in the aging nervous system.

Role of Calcium in Aging-Related Neurodegeneration

Aging is the greatest risk factor for the development of neurodegenerative disorders. These include a diverse collection of pathologies characterized by the late onset and gradual loss of specific neuronal subpopulations in motor, sensory, or cognitive systems. Despite major intrinsic differences in the etiology of each disorder, deregulated Ca2+ homeostasis has emerged as a common underlying mechanism of neuronal loss in AD, Parkinson’s (PD) diseases, amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders (Mattson, 2007; Bezprozvanny, 2009).

Alterations of Ca2+ homeostasis may be in some cases directly responsible for neuronal death. Persistently increased levels of intracellular Ca2+ can result in severe phenotypes in neurons, culminating to neuronal death and degeneration (Siman et al., 1989; Celsi et al., 2009). This process is often specifically mediated or even initiated by the diminished capacity of mitochondria to buffer Ca2+. An example where there is ample evidence that altered mitochondrial Ca2+ homeostasis mediates neuronal loss is ALS, an adult onset disease, with incidence increasing with age. ALS is characterized by selective and progressive degeneration of motorneurons in the spinal cord and brain, leading to weakness, atrophy, and paralysis of voluntary muscles. Mutations in superoxide dismutase (SOD1) are the most common genetic factors responsible for about 20% of familial ALS cases (Rosen et al., 1993). SOD1 is a ubiquitously expressed enzyme that converts superoxide to hydrogen peroxide in order to protect cells against oxidative stress. While there is still no consensus as to how mutant SOD1 causes selective toxicity to motorneurons, increasing evidence suggests that the mechanisms largely concentrate on the dysfunction of ER and mitochondrial Ca2+ homeostasis (Bacman et al., 2006; Hervias et al., 2006; Magrane et al., 2009; Shi et al., 2010).

At the level of the ER, a recent paper implicates the Ca2+ buffering protein calreticulin in the death of motorneurons in a model of ALS (Bernard-Marissal et al., 2012). More specifically, fast fatigable motorneurons selectively activate an ER stress response that drives their early degeneration, while a subset of mSOD1 motorneurons shows exacerbated sensitivity to activation of the motorneuron-specific Fas (transmembrane TNF receptor superfamily member 6) and nitric oxide (NO) pathway. However, the links between the two mechanisms and the molecular basis of their cellular specificity remained unclear. This paper demonstrates that Fas activation causes reduced levels of calreticulin specifically in mSOD1 motorneurons. Decreased expression of calreticulin is both necessary and sufficient to trigger SOD1(G93A) motorneuron death through the Fas/NO signaling pathway, and represents an early event that precedes muscle denervation and is restricted to vulnerable motor pools.

At the mitochondrial level, altered Ca2+ handling also appears early on, before motorneuron degeneration is manifested, suggesting that it is actively involved in disease pathogenesis. SOD1, which is a predominantly cytosolic protein, also localizes to the ER and mitochondria (Jaarsma et al., 2001; Okado-Matsumoto and Fridovich, 2001; Higgins et al., 2002; Mattiazzi et al., 2002), predominantly in the intermembrane space and less so on the outer membrane (Pasinelli et al., 2004; Vande Velde et al., 2008) and matrix (Vijayvergiya et al., 2005). By mechanisms that are still poorly understood, mutant SOD1 induces increased Ca2+ uptake by mitochondria, as convincingly demonstrated in mitochondria isolated from the brain and spinal cord of SOD1 mutant mice (Damiano et al., 2006). This defect appears to be neuron-specific, as liver cells from the same mutants retain unaffected mitochondrial Ca2+ homeostasis. Impaired Ca2+ handling by mitochondria is thought to be the primary cause of the abnormally high concentration of intracellular Ca2+ observed in ALS motorneurons (Carri et al., 1997; Kruman et al., 1999), making them vulnerable to degeneration (Kim et al., 2002,2007).

Mitochondrial Ca2+ overload is associated with activation of cell death pathways (Bernardi et al., 1999) and is observed in many pathological conditions in addition to ALS (Honda and Ping, 2006; Norenberg and Rao, 2007). The mechanisms responsible for Ca2+ overload are not entirely clear; however, their elucidation could provide a base for significant pharmacological interventions in the future. Theoretically, defects of the mitochondrial NCX could be involved in causing Ca2+ overload in ALS, although this putative mechanism remains to be directly explored. Another potential factor contributing to Ca2+ overload could be the functional and physical link between mitochondria and ER. Transfer of Ca2+ from the large stores in the ER to mitochondria depends on the relative positioning of these two organelles, and it is thought to occur at Ca2+ “hotspots”, sites where ER and mitochondrial membranes are in close physical contact (Rizzuto et al., 1999). Shortening the distance between the two organelles was shown to result in increased accumulation of Ca2+ in mitochondria, causing cell death (Csordas et al., 2006). Since mutant SOD1 accumulates both in ER (Kikuchi et al., 2006; Urushitani et al., 2006) and mitochondrial (Liu et al., 2004) membranes, it is plausible that the structure of these calcium hotspots is altered in mutant neurons, leading to abnormal handling of Ca2+ between the two organelles.

Whatever the mechanism of the increased Ca2+ accumulation in mitochondria, activation of cell death by mitochondrial Ca2+ overload involves the opening of the mPTP, followed by release of cytochrome c, and downstream activation of apoptosis. Cytochrome c released into the cytosol can further propagate apoptotic signaling by binding to the IP3-R on the ER, desensitizing its autoinhibition by calcium and thus causing further calcium release from ER stores (Boehning et al., 2003). Ablation of cyclophilin D (CypD), a modulatory component of the mPTP, delays the opening of mPTP (Basso et al., 2005) and has a protective effect against neuronal death in models of ischemia (Baines et al., 2005; Schinzel et al., 2005). In ALS, it was also reported that loss of CypD in SOD1 mutant mice delays the onset of the disease and significantly extends lifespan (Martin et al., 2009). Moreover, two studies using the immunosuppressant cyclosporin A, which binds to CypD to inhibit mPTP, in mutant SOD1 mice, suggest that inhibition of mPTP may be of benefit to ALS (Keep et al., 2001; Kirkinezos et al., 2004).

Another mechanism whereby Ca2+ contributes to the activation of cell death is by stimulating the production of mitochondrial reactive oxygen species (ROS). Oxidative stress caused by the damaging effect of ROS to proteins, lipids, and DNA, is a common feature of aging-related diseases, including ALS (Floyd and Hensley, 2002; Lin and Beal, 2006). Mitochondrial dysfunction (Wei, 1998), and particularly mitochondrial Ca2+ overload (Petrosillo et al., 2004), increases ROS production. In particular, increased levels of mitochondrial Ca2+ enhance cytochrome c release through a mechanism involving ROS-mediated oxidation of cardiolipin (Vercesi et al., 1997; Iverson and Orrenius, 2004). Notably, lipid peroxidation (Mattiazzi et al., 2002) and dissociation of cytochrome c from the mitochondrial inner membrane (Kirkinezos et al., 2005) have been reported in mutant SOD1 mice, but also in PD (Beal, 2003), and AD (Green and Kroemer, 2004;Lin and Beal, 2006; Kawamoto et al., 2012; Lee et al., 2012a).

Alzheimer’s disease is perhaps the most widespread neurodegenerative disorder of the elderly, with most familiar cases attributed to several mutations in presenilin 1 and 2, genes whose protein products are responsible for the proteolytic cleavage of the amyloid precursor peptide (APP). The mechanism by which presenilin mutations cause AD involves increased production of Aβ1–42 which aggregates and damages neurons. This view has been recently expanded by emerging findings suggesting that perturbed ER Ca2+ homeostasis significantly contributes to the dysfunction and degeneration of neurons in AD (Kipanyula et al., 2012). For example, recent work indicates that there is impaired Ca2+ uptake by mitochondria in the dentate gyrus of a mouse model of AD (Lee et al., 2012b). This can be explained to some extent by the novel role proposed by at least two groups for presenilins as regulators of Ca2+ homeostasis in the ER (Pack-Chung et al., 2000; Yoo et al., 2000). Interestingly, mutations in presenilin 1 that cause early onset familial AD, increase the pool of ER Ca2+ available for release, and enhance Ca2+ release from the ER through IP3- and RyR receptors (Chan et al., 2000; Guo et al., 1996,1999; Cheung et al., 2010; Leissring et al., 2000). Future research should clarify the specific contributions of perturbed ER Ca2+ handling to the cellular events that underlie synaptic dysfunction and neuronal degeneration in AD. While elevated pools of ER Ca2+ resulting from mutations in presenilins have been widely documented in a range of cell culture and animal models, the molecular basis of this alteration remains unknown and is potentially a key field for the development of novel pharmacological targets.

In addition to direct effects on neuronal survival, altered Ca2+ homeostasis is also likely to contribute to the initiation or progression of the neurodegenerative process by enhancing neuronal vulnerability to metabolic and other stressors (Toescu and Verkhratsky, 2004; Toescu and Vreugdenhil, 2010). One such example is the population of basal forebrain cholinergic neurons, a group of neurons that are selectively vulnerable to pathology and loss early in AD, as well as in a number of other neurodegenerative disorders of the elderly. In the primate, including man, these neurons are rich in the Ca2+ buffer protein calbindin. Notably, there is a substantial loss of calbindin in the course of normal aging and a further loss in AD(Iacopino and Christakos, 1990). Significantly, cholinergic neurons that had lost their calbindin in the course of normal aging were those that selectively degenerated in AD, while calbindin-containing neighboring neurons were virtually resistant to the process of tangle formation, a hallmark of the disease (Riascos et al., 2011). Another study reported that over-expression of calbindin in presenilin 1 mutant neurons was sufficient to prevent apoptosis (Guo et al., 1998). Similarly, a dramatic reduction in the Ca2+ buffering protein calbindin levels has been described in brains of PD patients (Iacopino and Christakos, 1990) and dopaminergic (DA) neurons expressing higher levels of calbindin, or other Ca2+ buffers such as calretinin and parvalbumin, were shown to be resistant to degeneration in PD (Yamada et al., 1990; Tsuboi et al., 2000). These findings are consistent with earlier findings suggesting that calbindin-positive hippocampal neurons are more resistant against oxidative stress (Mattson et al., 1991), although other Ca2+ buffer proteins seem to confer resistance to stress in different neuronal subpopulations. Understanding the mechanisms underlying such an instructive function of Ca2+ buffer proteins is of great importance as there may be a yet unidentified crosstalk with major signaling cascades. More work in this direction would greatly enhance our ability to selectively intervene in order to modulate the vulnerability of distinct neuronal populations.

Similar to ALS and AD, PD is another case where Ca2+ deregulation has recently attracted a lot of attention. PD is characterized by motor defects resulting from the selective loss of DA neurons in the substantia nigra and intracellular accumulation of cell aggregates known as Lewy bodies, mostly composed of α-synuclein. The idea that mitochondria could be directly involved in the pathogenesis of PD comes from the early accidental observation that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an inhibitor of the mitochondrial respiratory chain complex I, causes Parkinson-like symptoms (Langston and Ballard, 1983). Later on, it was also demonstrated that DA neurons from PD patients show massive accumulation of mitochondrial DNA (mtDNA) deletions that impair the function of the respiratory chain complexes (Exner et al., 2012), thus increasing the probability of dysfunctions in these organelles.

Some clues as to the selective vulnerability of this population arise from the fact that DA neurons of the substantia nigra display unusual physiological properties. First, unlike most other neurons in the brain, they are autonomously active, generating regular action potentials in the absence of synaptic input (Grace and Bunney, 1983). This pacemaking activity is thought to maintain physiological levels of dopamine in regions they innervate, particularly the striatum (Romo and Schultz, 1990). To drive this pacemaking activity, these neurons rely, at least in part, on a rare form of L-type Ca2+ channels (Bonci et al., 1998; Ping and Shepard, 1996; Puopolo et al., 2007) comprised of the Cav1.3 pore-forming subunit (Striessnig et al., 2006; Chan et al., 2007). This leads to typically elevated intracellular Ca2+ concentrations under physiological conditions (Wilson and Callaway, 2000; Chan et al., 2007). Second, DA neurons of the substantia nigra display an elaborate axonal network (Matsuda et al., 2009), supporting orders of magnitude more synapses compared to a cortical pyramidal neuron (Arbuthnott and Wickens, 2007). As a result, the mitochondrial density in their somatic and dendritic regions is very low compared to other neuronal types (Liang et al., 2007). Taken together, these characteristics are thought to contribute to an intrinsic state of increased metabolic stress, where increased load of intracellular Ca2+ is met by a depleted mitochondrial network.

Additional genetic factors could increase the rate at which mitochondrial Ca2+ homeostasis is compromised in these already vulnerable neurons. At least 13 gene loci and 9 genes have been linked to both autosomal dominant and recessive forms of PD (Lesage and Brice, 2009). Mutations in three proteins encoded by these genes, namely, parkin (PARK2), DJ-1 (PARK7), and PINK1 (PARK6), are associated with recessive early onset forms of PD, whereas mutations in α-synuclein (PARK1–4) and LRRK2 (PARK8) are responsible for dominant forms of familial PD. Mitochondrial dysfunction has been described for mutants of all these genes (Lesage and Brice, 2009).

Recent papers have started to explore in more detail the possibility of Ca2+ handling by the PD-related proteins. DJ-1 is a multitask protein that, in addition to its main role as an antioxidant (Taira et al., 2004), is also involved in maintaining cytosolic basal Ca2+ concentration values to permit depolarization-induced Ca2+ release from the sarcoplasmic reticulum in muscle cells (Shtifman et al., 2011). Moreover, DJ-1 was shown to protect DA neurons from Ca2+-induced mitochondrial uncoupling and ROS production during physiological pacemaking (Guzman et al., 2010).

Regarding α-synuclein, it has been described that it can modulate Ca2+ influx from the extracellular milieu by enhancing the plasma membrane ion permeability (Danzer et al., 2007) either through their direct insertion into the plasma membrane and the formation of a pore (Lashuel et al., 2002) or through the modulation of plasma membrane Ca2+ permeability (Furukawa et al., 2006). The actual mechanisms through which α-synuclein aggregation and Ca2+ dysfunction influence each other are not clear, however, a functional interplay is unambiguous: Increased intracellular Ca2+ promotes α-synuclein aggregation, which in turn could promote intracellular Ca2+ increase (Nath et al., 2011). A recent study suggests that using its C-terminal domain, α-synuclein controls mitochondrial calcium homeostasis by enhancing ER–mitochondria interactions (Cali et al., 2012). As these results were obtained in vitro using non-neuronal cell lines, their relevance to DA neuron physiology and pathology remains to be examined.

As to PINK1, its direct role in regulating cellular, and most specifically mitochondrial Ca2+ fluxes, has been recently proposed starting with the observation that the co-expression of mutant PINK1 in a cellular model of PD-expressing mutated α-synuclein exacerbated the observed mitochondrial defects, that is, increased mitochondrial size with loss of cristae and reduced ATP levels (Marongiu et al., 2009). The proposed mechanisms of PINK1 action was based on a deregulation of mitochondrial Ca2+ influx. As by blocking mitochondrial Ca2+ uptake, it was possible to restore the original phenotype (Marongiu et al., 2009), thus suggesting that mutant PINK1 could reinforce α-synuclein pathology by acting on converging pathways affecting mitochondrial function. Other studies have further investigated the role of PINK1 in mitochondrial Ca2+ metabolism, but the results are controversial. In one case, it was proposed that PINK1 absence caused an impairment of mitochondrial Ca2+ efflux, probably affecting the mitochondrial Na+/Ca2+ exchanger activity and thus resulting in mitochondrial Ca2+ overload, ROS production, and impaired respiration (Gandhi et al., 2009). In another very recent study, PINK1 depletion has instead been shown to impair mitochondrial Ca2+ uptake and consequently to affect energy metabolism (Heeman et al., 2011). However, consistently, numerous reports showed that PINK1-deficient cells have impaired mitochondrial membrane potential and enhanced sensitivity to the toxic effects of mitochondrial complex I inhibitors (Wood-Kaczmar et al., 2008), as well as enhanced Ca2+ vulnerability (Akundi et al., 2011).

Outlook

Given the fundamental importance of Ca2+ homeostasis in the biology of all cells, it is not completely surprising that more and more studies suggest that deregulated Ca2+ is actively involved in the course of normal aging and in diverse pathological conditions. A general message arising from these studies is that in the nervous system Ca2+ signaling and homeostasis should be examined in view of the amazing cellular diversity exhibited by the nervous system. The machinery controlling Ca2+ homeostasis is similarly diverse among neurons, uniquely suited to the needs of each neuronal subtype. Taken together, the intrinsic differences of neurons in morphology, connectivity, proteome and Ca2+ homeostatic machinery are very likely to collectively and synergistically contribute to the selective vulnerability of distinct neuronal populations to different causes of senescence. The more we understand the interplay of Ca2+ homeostatic mechanisms with the intrinsic qualities of different neurons, the closer we will get to developing cell-specific therapies.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potentialconflict of interest.

Acknowledgments

Work in the authors’ laboratory is funded by grants from the European Research Council (ERC), the European Commission Framework Programmes, and the Greek Ministry of Education. Vassiliki Nikoletopoulou is supported by an EMBO long-term postdoctoral fellowship.

References

Akundi, R. S., Huang, Z., Eason, J., Pandya, J. D., Zhi, L., Cass, W. A., et al. (2011). Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS ONE 6, e16038. doi: 10.1371/journal.pone.0016038

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Arbuthnott, G. W., and Wickens, J. (2007). Space, time and dopamine. Trends Neurosci. 30, 62–69.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Artola, A., and Singer, W. (1993). Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation. Trends Neurosci. 16, 480–487.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Atluri, P. P., and Regehr, W. G. (1998). Delayed release of neurotransmitter from cerebellar granule cells. J. Neurosci. 18, 8214–8227.

Pubmed Abstract | Pubmed Full Text

Bacman, S. R., Bradley, W. G., and Moraes, C. T. (2006). Mitochondrial involvement in amyotrophic lateral sclerosis: trigger or target? Mol. Neurobiol. 33, 113–131.

CrossRef Full Text

Baines, C. P., Kaiser, R. A., Purcell, N. H., Blair, N. S., Osinska, H., Hambleton, M. A., et al. (2005). Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658–662.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bajjalieh, S. M., and Scheller, R. H. (1995). The biochemistry of neurotransmitter secretion. J. Biol. Chem. 270, 1971–1974.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bak, J., White, P., Timar, G., Missiaen, L., Genazzani, A. A., and Galione, A. (1999). Nicotinic acid adenine dinucleotide phosphate triggers Ca2+ release from brain microsomes. Curr. Biol. 9, 751–754.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Baker, P. F., and Allen, T. J. (1984). The voltage-sensitivity of Na–Ca exchange in the squid axon. Prog. Clin. Biol. Res. 168, 89–94.

Pubmed Abstract | Pubmed Full Text

Ban, T. A., Morey, L., Aguglia, E., Azzarelli, O., Balsano, F., Marigliano, V., et al. (1990). Nimodipine in the treatment of old age dementias. Prog. Neuropsychopharmacol. Biol. Psychiatry 14, 525–551.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Barnes, C. A. (1994). Normal aging: regionally specific changes in hippocampal synaptic transmission. Trends Neurosci. 17, 13–18.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Barrett, E. F., and Stevens, C. F. (1972). The kinetics of transmitter release at the frog neuromuscular junction. J. Physiol. 227, 691–708.

Pubmed Abstract | Pubmed Full Text

Basso, E., Fante, L., Fowlkes, J., Petronilli, V., Forte, M. A., and Bernardi, P. (2005). Properties of the permeability transition pore in mitochondria devoid of cyclophilin D. J. Biol. Chem. 280, 18558–18561.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Beal, M. F. (2003). Mitochondria, oxidative damage, and inflammation in Parkinson’s disease. Ann. N. Y. Acad. Sci. 991, 120–131.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Behne, M. J., Tu, C. L., Aronchik, I., Epstein, E., Bench, G., Bikle, D. D., et al. (2003). Human keratinocyte ATP2C1 localizes to the Golgi and controls Golgi Ca2Ca2+ stores. J. Invest. Dermatol. 121, 688–694.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bernard-Marissal, N., Moumen, A., Sunyach, C., Pellegrino, C., Dudley, K., Henderson, C. E., et al. (2012). Reduced calreticulin levels link endoplasmic reticulum stress and Fas-triggered cell death in motoneurons vulnerable to ALS. J. Neurosci. 32, 4901–4912.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bernardi, P., Scorrano, L., Colonna, R., Petronilli, V., and Di Lisa, F. (1999). Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur. J. Biochem. 264, 687–701.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Berridge, M. J. (1998). Neuronal calcium signaling. Neuron 21, 13–26.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bezprozvanny, I. (2009). Calcium signaling and neurodegenerative diseases. Trends Mol. Med. 15, 89–100.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Blaustein, M. P. (1988). Sodium/calcium exchange and the control of contractility in cardiac muscle and vascular smooth muscle. J. Cardiovasc. Pharmacol. 12(Suppl. 5), S56–S68.

Pubmed Abstract | Pubmed Full Text

Blaustein, M. P., Juhaszova, M., Golovina, V. A., Church, P. J., and Stanley, E. F. (2002). Na/Ca exchanger and PMCA localization in neurons and astrocytes: functional implications. Ann. N. Y. Acad. Sci. 976, 356–366.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bliss, T. V., and Collingridge, G. L. (1993). A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bodhinathan, K., Kumar, A., and Foster, T. C. (2010). Redox sensitive calcium stores underlie enhanced after hyperpolarization of aged neurons: role for ryanodine receptor mediated calcium signaling. J. Neurophysiol. 104, 2586–2593.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Boehning, D., Patterson, R. L., Sedaghat, L., Glebova, N. O., Kurosaki, T., and Snyder, S. H. (2003). Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat. Cell Biol. 5, 1051–1061.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bonci, A., Grillner, P., Mercuri, N. B., and Bernardi, G. (1998). L-type calcium channels mediate a slow excitatory synaptic transmission in rat midbrain dopaminergic neurons. J. Neurosci. 18, 6693–6703.

Pubmed Abstract | Pubmed Full Text

Braunewell, K. H., and Gundelfinger, E. D. (1999). Intracellular neuronal calcium sensor proteins: a family of EF-hand calcium-binding proteins in search of a function. Cell Tissue Res. 295, 1–12.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Burgoyne, R. D., and Weiss, J. L. (2001). The neuronal calcium sensor family of Ca2+-binding proteins. Biochem. J. 353, 1–12.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Buxbaum, J. D. (2004). A role for calsenilin and related proteins in multiple aspects of neuronal function. Biochem. Biophys. Res. Commun. 322, 1140–1144.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Buxbaum, J. D., Choi, E. K., Luo, Y., Lilliehook, C., Crowley, A. C., Merriam, D. E., et al. (1998). Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment. Nat. Med. 4, 1177–1181.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cali, T., Ottolini, D., Negro, A., and Brini, M. (2012). Alpha-synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum–mitochondria interactions. J. Biol. Chem. 287, 17914–17929.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Callewaert, G., Parys, J. B., De Smedt, H., Raeymaekers, L., Wuytack, F., Vanoevelen, J., et al. (2003). Similar Ca(2+)-signaling properties in keratinocytes and in COS-1 cells overexpressing the secretory-pathway Ca(2+)-ATPase SPCA1. Cell Calcium 34, 157–162.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Camello, C., Lomax, R., Petersen, O. H., and Tepikin, A. V. (2002). Calcium leak from intracellular stores – the enigma of calcium signalling. Cell Calcium 32, 355–361.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Carafoli, E., and Longoni, S. (1987). The plasma membrane in the control of the signaling function of calcium. Soc. Gen. Physiol. Ser. 42, 21–29.

Pubmed Abstract | Pubmed Full Text

Carri, M. T., Ferri, A., Battistoni, A., Famhy, L., Gabbianelli, R., Poccia, F., et al. (1997). Expression of a Cu,Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis induces mitochondrial alteration and increase of cytosolic Ca2+ concentration in transfected neuroblastoma SH-SY5Y cells. FEBS Lett. 414, 365–368.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Carrion, A. M., Link, W. A., Ledo, F., Mellstrom, B., and Naranjo, J. R. (1999). DREAM is a Ca2+-regulated transcriptional repressor. Nature 398, 80–84.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Catterall, W. A., Nunoki, K., Lai, Y., De Jongh, K., Thomsen, W., and Rossie, S. (1990). Structure and modulation of voltage-sensitive sodium and calcium channels. Adv. Second Messenger Phosphoprotein Res. 24, 30–35.

Pubmed Abstract | Pubmed Full Text

Celsi, F., Pizzo, P., Brini, M., Leo, S., Fotino, C., Pinton, P., et al. (2009). Mitochondria, calcium and cell death: a deadly triad in neurodegeneration. Biochim. Biophys. Acta 1787, 335–344.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chalfie, M., and Wolinsky, E. (1990). The identification and suppression of inherited neurodegeneration in Caenorhabditis elegans. Nature 345, 410–416.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chameau, P., Van de Vrede, Y., Fossier, P., and Baux, G. (2001). Ryanodine-, IP3- and NAADP-dependent calcium stores control acetylcholine release. Pflugers Arch. 443, 289–296.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chan, C. S., Guzman, J. N., Ilijic, E., Mercer, J. N., Rick, C., Tkatch, T., et al. (2007). ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature 447, 1081–1086.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chan, S. L., Mayne, M., Holden, C. P., Geiger, J. D., and Mattson, M. P. (2000). Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J. Biol. Chem. 275, 18195–18200.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cheung, K. H., Mei, L., Mak, D. O., Hayashi, I., Iwatsubo, T., Kang, D. E., et al. (2010). Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer’s disease-linked presenilin mutants in human cells and mouse neurons. Sci. Signal. 3, ra22.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Contreras, L., Drago, I., Zampese, E., and Pozzan, T. (2010). Mitochondria: the calcium connection. Biochim. Biophys. Acta 1797, 607–618.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Csordas, G., Renken, C., Varnai, P., Walter, L., Weaver, D., Buttle, K. F., et al. (2006). Structural and functional features and significance of the physical linkage between ER and mitochondria. J. Cell Biol. 174, 915–921.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Damiano, M., Starkov, A. A., Petri, S., Kipiani, K., Kiaei, M., Mattiazzi, M., et al. (2006). Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice. J. Neurochem. 96, 1349–1361.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Danzer, K. M., Haasen, D., Karow, A. R., Moussaud, S., Habeck, M., Giese, A., et al. (2007). Different species of alpha-synuclein oligomers induce calcium influx and seeding. J. Neurosci. 27, 9220–9232.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Davare, M. A., and Hell, J. W. (2003). Increased phosphorylation of the neuronal L-type Ca(2+) channel Ca(v)1.2 during aging. Proc. Natl. Acad. Sci. U.S.A. 100, 16018–16023.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Dekkers, J., Bayley, P., Dick, J. R., Schwaller, B., Berchtold, M. W., and Greensmith, L. (2004). Over-expression of parvalbumin in transgenic mice rescues motoneurons from injury-induced cell death. Neuroscience 123, 459–466.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Del Arco, A., Agudo, M., and Satrustegui, J. (2000). Characterization of a second member of the subfamily of calcium-binding mitochondrial carriers expressed in human non-excitable tissues. Biochem. J. 345(Pt 3), 725–732.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

del Arco, A., and Satrustegui, J. (1998). Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain. J. Biol. Chem. 273, 23327–23334.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Deyo, R. A., Straube, K. T., Moyer, J. R. Jr., and Disterhoft, J. F. (1989). Nimodipine ameliorates aging-related changes in open-field behaviors of the rabbit. Exp. Aging Res. 15, 169–175.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Di Leva, F., Domi, T., Fedrizzi, L., Lim, D., and Carafoli, E. (2008). The plasma membrane Ca2+ ATPase of animal cells: structure, function and regulation. Arch. Biochem. Biophys. 476, 65–74.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

DiPolo, R., and Beauge, L. (1983). The calcium pump and sodium-calcium exchange in squid axons. Annu. Rev. Physiol. 45, 313–324.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Disterhoft, J. F., Moyer, J. R. Jr., and Thompson, L. T. (1994). The calcium rationale in aging and Alzheimer’s disease. Evidence from an animal model of normal aging. Ann. N. Y. Acad. Sci. 747, 382–406.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Dizhoor, A. M., Boikov, S. G., and Olshevskaya, E. V. (1998). Constitutive activation of photoreceptor guanylate cyclase by Y99C mutant of GCAP-1. Possible role in causing human autosomal dominant cone degeneration. J. Biol. Chem. 273, 17311–17314.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Dunlap, K., Luebke, J. I., and Turner, T. J. (1995). Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci. 18, 89–98.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ernfors, P., Bengzon, J., Kokaia, Z., Persson, H., and Lindvall, O. (1991). Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis. Neuron 7, 165–176.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ertel, E. A., Campbell, K. P., Harpold, M. M., Hofmann, F., Mori, Y., Perez-Reyes, E., et al. (2000). Nomenclature of voltage-gated calcium channels. Neuron 25, 533–535.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Exner, N., Lutz, A. K., Haass, C., and Winklhofer, K. F. (2012). Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J. 31, 3038–3062.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Fairclough, R. J., Dode, L., Vanoevelen, J., Andersen, J. P., Missiaen, L., Raeymaekers, L., et al. (2003). Effect of Hailey–Hailey disease mutations on the function of a new variant of human secretory pathway Ca2+/Mn2+-ATPase (hSPCA1). J. Biol. Chem. 278, 24721–24730.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Fink, C. C., and Meyer, T. (2002). Molecular mechanisms of CaMKII activation in neuronal plasticity. Curr. Opin. Neurobiol. 12, 293–299.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Fitzpatrick, J. S., Hagenston, A. M., Hertle, D. N., Gipson, K. E., Bertetto-D’Angelo, L., and Yeckel, M. F. (2009). Inositol-1,4,5-trisphosphate receptor-mediated Ca2+ waves in pyramidal neuron dendrites propagate through hot spots and cold spots. J. Physiol. 587, 1439–1459.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Floyd, R. A., and Hensley, K. (2002). Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol. Aging 23, 795–807.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Fluegge, D., Moeller, L. M., Cichy, A., Gorin, M., Weth, A., Veitinger, S., et al. (2012). Mitochondrial Ca(2+) mobilization is a key element in olfactory signaling. Nat. Neurosci. 15, 754–762.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Foster, T. C. (1999). Involvement of hippocampal synaptic plasticity in age-related memory decline. Brain Res. Brain Res. Rev. 30, 236–249.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Foster, T. C. (2007). Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell 6, 319–325.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Foster, T. C., and Kumar, A. (2002). Calcium dysregulation in the aging brain. Neuroscientist 8, 297–301.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Foster, T. C., and Norris, C. M. (1997). Age-associated changes in Ca(2+)-dependent processes: relation to hippocampal synaptic plasticity. Hippocampus 7, 602–612.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Foster, T. C., Sharrow, K. M., Masse, J. R., Norris, C. M., and Kumar, A. (2001). Calcineurin links Ca2+ dysregulation with brain aging. J. Neurosci. 21, 4066–4073.

Pubmed Abstract | Pubmed Full Text

Furuichi, T., Furutama, D., Hakamata, Y., Nakai, J., Takeshima, H., and Mikoshiba, K. (1994). Multiple types of ryanodine receptor/Ca2+ release channels are differentially expressed in rabbit brain. J. Neurosci. 14, 4794–4805.

Pubmed Abstract | Pubmed Full Text

Furukawa, K., Matsuzaki-Kobayashi, M., Hasegawa, T., Kikuchi, A., Sugeno, N., Itoyama, Y., et al. (2006). Plasma membrane ion permeability induced by mutant alpha-synuclein contributes to the degeneration of neural cells. J. Neurochem. 97, 1071–1077.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gallagher, M., Landfield, P. W., McEwen, B., Meaney, M. J., Rapp, P. R., Sapolsky, R., et al. (1996). Hippocampal neurodegeneration in aging. Science 274, 484–485.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gandhi, S., Wood-Kaczmar, A., Yao, Z., Plun-Favreau, H., Deas, E., Klupsch, K., et al. (2009). PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol. Cell. 33, 627–638.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gant, J. C., Sama, M. M., Landfield, P. W., and Thibault, O. (2006). Early and simultaneous emergence of multiple hippocampal biomarkers of aging is mediated by Ca2+-induced Ca2+ release. J. Neurosci. 26, 3482–3490.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gao, J., Cohen, I. S., Mathias, R. T., and Baldo, G. J. (1998). The inhibitory effect of beta-stimulation on the Na/K pump current in guinea pig ventricular myocytes is mediated by a cAMP-dependent PKA pathway. Pflugers Arch. 435, 479–484.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ghosh, A., Carnahan, J., and Greenberg, M. E. (1994). Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263, 1618–1623.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gibson, G. E., and Peterson, C. (1987). Calcium and the aging nervous system. Neurobiol. Aging 8, 329–343.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Goda, Y., and Stevens, C. F. (1994). Two components of transmitter release at a central synapse. Proc. Natl. Acad. Sci. U.S.A. 91, 12942–12946.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Grace, A. A., and Bunney, B. S. (1983). Intracellular and extracellular electrophysiology of nigral dopaminergic neurons-2. Action potential generating mechanisms and morphological correlates. Neuroscience 10, 317–331.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Green, D. R., and Kroemer, G. (2004). The pathophysiology of mitochondrial cell death. Science 305, 626–629.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gunteski-Hamblin, A. M., Clarke, D. M., and Shull, G. E. (1992). Molecular cloning and tissue distribution of alternatively spliced mRNAs encoding possible mammalian homologues of the yeast secretory pathway calcium pump. Biochemistry 31, 7600–7608.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Guo, Q., Fu, W., Sopher, B. L., Miller, M. W., Ware, C. B., Martin, G. M., et al. (1999). Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat. Med. 5, 101–106.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Guo, Q., Christakos, S., Robinson, N., and Mattson, M. P. (1998). Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function. Proc. Natl. Acad. Sci. U.S.A. 95, 3227–3232.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Guo, Q., Furukawa, K., Sopher, B. L., Pham, D. G., Xie, J., Robinson, N., et al. (1996). Alzheimer’s PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide. Neuroreport 8, 379–383.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Guzman, J. N., Sanchez-Padilla, J., Wokosin, D., Kondapalli, J., Ilijic, E., Schumacker, P. T., et al. (2010). Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468, 696–700.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hagenston, A. M., Fitzpatrick, J. S., and Yeckel, M. F. (2008). MGluR-mediated calcium waves that invade the soma regulate firing in layer V medial prefrontal cortical pyramidal neurons. Cereb. Cortex 18, 407–423.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hagler, D. J. Jr., and Goda, Y. (2001). Properties of synchronous and asynchronous release during pulse train depression in cultured hippocampal neurons. J. Neurophysiol. 85, 2324–2334.

Pubmed Abstract | Pubmed Full Text

Hakamata, Y., Nakai, J., Takeshima, H., and Imoto, K. (1992). Primary structure and distribution of a novel ryanodine receptor/calcium release channel from rabbit brain. FEBS Lett. 312, 229–235.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Heeman, B., Van den Haute, C., Aelvoet, S. A., Valsecchi, F., Rodenburg, R. J., Reumers, V., et al. (2011). Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance. J. Cell Sci. 124, 1115–1125.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Herman, J. P., Chen, K. C., Booze, R., and Landfield, P. W. (1998). Up-regulation of alpha1D Ca2+ channel subunit mRNA expression in the hippocampus of aged F344 rats. Neurobiol. Aging 19, 581–587.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hertle, D. N., and Yeckel, M. F. (2007). Distribution of inositol-1,4,5-trisphosphate receptor isotypes and ryanodine receptor isotypes during maturation of the rat hippocampus. Neuroscience 150, 625–638.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hervias, I., Beal, M. F., and Manfredi, G. (2006). Mitochondrial dysfunction and amyotrophic lateral sclerosis. Muscle Nerve 33, 598–608.

CrossRef Full Text

Higgins, C. M., Jung, C., Ding, H., and Xu, Z. (2002). Mutant Cu, Zn superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the CNS. J. Neurosci. 22, RC215.

Pubmed Abstract | Pubmed Full Text

Honda, H. M., and Ping, P. (2006). Mitochondrial permeability transition in cardiac cell injury and death. Cardiovasc. Drugs Ther. 20, 425–432.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hu, Z., Bonifas, J. M., Beech, J., Bench, G., Shigihara, T., Ogawa, H., et al. (2000). Mutations in ATP2C1, encoding a calcium pump, cause Hailey–Hailey disease. Nat. Genet. 24, 61–65.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hubbard, J. I. (1963). Repetitive stimulation at the mammalian neuromuscular junction, and the mobilization of transmitter. J. Physiol. 169, 641–662.

Pubmed Abstract | Pubmed Full Text

Iacopino, A. M., and Christakos, S. (1990). Specific reduction of calcium-binding protein (28-kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases. Proc. Natl. Acad. Sci. U.S.A. 87, 4078–4082.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ichas, F., Jouaville, L. S., and Mazat, J. P. (1997). Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell 89, 1145–1153.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ishikawa, K., Nagase, T., Suyama, M., Miyajima, N., Tanaka, A., Kotani, H., et al. (1998). Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5, 169–176.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Iverson, S. L., and Orrenius, S. (2004). The cardiolipin-cytochrome c interaction and the mitochondrial regulation of apoptosis. Arch. Biochem. Biophys. 423, 37–46.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Jaarsma, D., Rognoni, F., van Duijn, W., Verspaget, H. W., Haasdijk, E. D., and Holstege, J. C. (2001). CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol. 102, 293–305.

Pubmed Abstract | Pubmed Full Text

Joiner, M. A., and Griffith, L. C. (1999). Mapping of the anatomical circuit of CaM kinase-dependent courtship conditioning in Drosophila. Learn. Mem. 6, 177–192.

Pubmed Abstract | Pubmed Full Text

Juhaszova, M., Church, P., Blaustein, M. P., and Stanley, E. F. (2000). Location of calcium transporters at presynaptic terminals. Eur. J. Neurosci. 12, 839–846.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kamal, A., Biessels, G. J., Duis, S. E., and Gispen, W. H. (2000). Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing. Diabetologia 43, 500–506.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kapur, A., Yeckel, M., and Johnston, D. (2001). Hippocampal mossy fiber activity evokes Ca2+ release in CA3 pyramidal neurons via a metabotropic glutamate receptor pathway. Neuroscience 107, 59–69.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kawamoto, Y., Ito, H., Ihara, M., and Takahashi, R. (2012). Immunohistochemical localization of X-linked inhibitor of apoptosis protein in brainstem-type and cortical Lewy bodies. Neuroreport 23, 162–167.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Keep, M., Elmer, E., Fong, K. S., and Csiszar, K. (2001). Intrathecal cyclosporin prolongs survival of late-stage ALS mice. Brain Res. 894, 327–331.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Khachaturian, Z. S. (1989). Calcium, membranes, aging, and Alzheimer’s disease. Introduction and overview. Ann. N. Y. Acad. Sci. 568, 1–4.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Khachaturian, Z. S. (1994). Calcium hypothesis of Alzheimer’s disease and brain aging. Ann. N. Y. Acad. Sci. 747, 1–11.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kikuchi, H., Almer, G., Yamashita, S., Guegan, C., Nagai, M., Xu, Z., et al. (2006). Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc. Natl. Acad. Sci. U.S.A. 103, 6025–6030.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kim, D., Nguyen, M. D., Dobbin, M. M., Fischer, A., Sananbenesi, F., Rodgers, J. T., et al. (2007). SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169–3179.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kim, H. J., Kim, M., Kim, S. H., Sung, J. J., and Lee, K. W. (2002). Alteration in intracellular calcium homeostasis reduces motor neuronal viability expressing mutated Cu/Zn superoxide dismutase through a nitric oxide/guanylyl cyclase cGMP cascade. Neuroreport 13, 1131–1135.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kipanyula, M. J., Contreras, L., Zampese, E., Lazzari, C., Wong, A. K., Pizzo, P., et al. (2012). Ca(2+) dysregulation in neurons from transgenic mice expressing mutant presenilin 2. Aging Cell 11, 885–893.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kirkinezos, I. G., Bacman, S. R., Hernandez, D., Oca-Cossio, J., Arias, L. J., Perez-Pinzon, M. A., et al. (2005). Cytochrome c association with the inner mitochondrial membrane is impaired in the CNS of G93A-SOD1 mice. J. Neurosci. 25, 164–172.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kirkinezos, I. G., Hernandez, D., Bradley, W. G., and Moraes, C. T. (2004). An ALS mouse model with a permeable blood-brain barrier benefits from systemic cyclosporine A treatment. J. Neurochem. 88, 821–826.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kourtis, N., Nikoletopoulou, V., and Tavernarakis, N. (2012). Small heat shock proteins protect from heat stroke-associated neurodegeneration. Nature doi: 10.1038/nature11417. [Epub ahead of print].

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kowalska, M., and Disterhoft, J. F. (1994). Relation of nimodipine dose and serum concentration to learning enhancement in aging rabbits. Exp. Neurol. 127, 159–166.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kretsinger, R. H. (1980). Crystallographic studies of calmodulin and homologs. Ann. N. Y. Acad. Sci. 356, 14–19.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kruman, II, Pedersen, W. A., Springer, J. E., and Mattson, M. P. (1999). ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis. Exp. Neurol. 160, 28–39.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kumar, A., and Foster, T. C. (2004). Enhanced long-term potentiation during aging is masked by processes involving intracellular calcium stores. J. Neurophysiol. 91, 2437–2444.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kumar, A., and Foster, T. C. (2005). Intracellular calcium stores contribute to increased susceptibility to LTD induction during aging. Brain Res. 1031, 125–128.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kurnellas, M. P., Lee, A. K., Li, H., Deng, L., Ehrlich, D. J., and Elkabes, S. (2007). Molecular alterations in the cerebellum of the plasma membrane calcium ATPase 2 (PMCA2)-null mouse indicate abnormalities in Purkinje neurons. Mol. Cell. Neurosci. 34, 178–188.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lai, F. A., Liu, Q. Y., Xu, L., el-Hashem, A., Kramarcy, N. R., Sealock, R., et al. (1992). Amphibian ryanodine receptor isoforms are related to those of mammalian skeletal or cardiac muscle. Am. J. Physiol. 263, C365–C372.

Pubmed Abstract | Pubmed Full Text

Landfield, P. W., and Pitler, T. A. (1984). Prolonged Ca2+-dependent afterhyperpolarizations in hippocampal neurons of aged rats. Science 226, 1089–1092.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Langston, J. W., and Ballard, P. A. Jr. (1983). Parkinson’s disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. N. Engl. J. Med. 309–310.

Pubmed Abstract | Pubmed Full Text

Larkum, M. E., Watanabe, S., Nakamura, T., Lasser-Ross, N., and Ross, W. N. (2003). Synaptically activated Ca2+ waves in layer 2/3 and layer 5 rat neocortical pyramidal neurons. J. Physiol. 549, 471–488.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lashuel, H. A., Petre, B. M., Wall, J., Simon, M., Nowak, R. J., Walz, T., et al. (2002). Alpha-synuclein, especially the Parkinson’s disease-associated mutants, forms pore-like annular and tubular protofibrils. J. Mol. Biol. 322, 1089–1102.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lechleiter, J., Girard, S., Peralta, E., and Clapham, D. (1991). Spiral calcium wave propagation and annihilation in Xenopus laevis oocytes. Science 252, 123–126.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lee, J. C., Shin, J. H., Park, B. W., Kim, G. S., Kim, J. C., Kang, K. S., et al. (2012a). Region-specific changes in the immunoreactivity of SIRT1 expression in the central nervous system of SOD1(G93A) transgenic mice as an in vivo model of amyotrophic lateral sclerosis. Brain Res. 1433, 20–28.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lee, S. H., Kim, K. R., Ryu, S. Y., Son, S., Hong, H. S., Mook-Jung, I., et al. (2012b). Impaired short-term plasticity in mossy fiber synapses caused by mitochondrial dysfunction of dentate granule cells is the earliest synaptic deficit in a mouse model of Alzheimer’s disease. J. Neurosci. 32, 5953–5963.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lehohla, M., Kellaway, L., and Russell, V. A. (2008). Effect of ageing on Ca2+ uptake via NMDA receptors into barrel cortex slices of spontaneously hypertensive rats. Metab. Brain Dis. 23, 1–8.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Leissring, M. A., Akbari, Y., Fanger, C. M., Cahalan, M. D., Mattson, M. P., and LaFerla, F. M. (2000). Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J. Cell Biol. 149, 793–798.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lesage, S., and Brice, A. (2009). Parkinson’s disease: from monogenic forms to genetic susceptibility factors. Hum. Mol. Genet. 18, R48–R59.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Levere, T. E., and Walker, A. (1992). Old age and cognition: enhancement of recent memory in aged rats by the calcium channel blocker nimodipine. Neurobiol. Aging 13, 63–66.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Liang, C. L., Wang, T. T., Luby-Phelps, K., and German, D. C. (2007). Mitochondria mass is low in mouse substantia nigra dopamine neurons: implications for Parkinson’s disease. Exp. Neurol. 203, 370–380.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lin, M. T., and Beal, M. F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lin, P., Le-Niculescu, H., Hofmeister, R., McCaffery, J. M., Jin, M., Hennemann, H., et al. (1998). The mammalian calcium-binding protein, nucleobindin (CALNUC), is a Golgi resident protein. J. Cell Biol. 141, 1515–1527.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lisman, J. (1989). A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. Proc. Natl. Acad. Sci. U.S.A. 86, 9574–9578.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lisman, J. (1994). The CaM kinase II hypothesis for the storage of synaptic memory. Trends Neurosci. 17, 406–412.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Liu, J., Lillo, C., Jonsson, P. A., Vande Velde, C., Ward, C. M., Miller, T. M., et al. (2004). Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron 43, 5–17.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Llinas, R., Steinberg, I. Z., and Walton, K. (1981). Presynaptic calcium currents in squid giant synapse. Biophys. J. 33, 289–321.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Llinas, R. R. (1988). The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function. Science 242, 1654–1664.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lu, T., and Trussell, L. O. (2000). Inhibitory transmission mediated by asynchronous transmitter release. Neuron 26, 683–694.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lynch, G., Larson, J., Kelso, S., Barrionuevo, G., and Schottler, F. (1983). Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature 305, 719–721.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ma, Z., Siebert, A. P., Cheung, K. H., Lee, R. J., Johnson, B., Cohen, A. S., et al. (2012). Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability. Proc. Natl. Acad. Sci. U.S.A. 109, E1963–E1971.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

MacDermott, A. B., Mayer, M. L., Westbrook, G. L., Smith, S. J., and Barker, J. L. (1986). NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature 321, 519–522.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Magrane, J., Hervias, I., Henning, M. S., Damiano, M., Kawamata, H., and Manfredi, G. (2009). Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities. Hum. Mol. Genet. 18, 4552–4564.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Malenka, R. C., Kauer, J. A., Perkel, D. J., and Nicoll, R. A. (1989). The impact of postsynaptic calcium on synaptic transmission – its role in long-term potentiation. Trends Neurosci. 12, 444–450.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Malenka, R. C., Kauer, J. A., Zucker, R. S., and Nicoll, R. A. (1988). Postsynaptic calcium is sufficient for potentiation of hippocampal synaptic transmission. Science 242, 81–84.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Marongiu, R., Spencer, B., Crews, L., Adame, A., Patrick, C., Trejo, M., et al. (2009). Mutant Pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson’s disease by disturbing calcium flux. J. Neurochem. 108, 1561–1574.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Martin, L. J., Gertz, B., Pan, Y., Price, A. C., Molkentin, J. D., and Chang, Q. (2009). The mitochondrial permeability transition pore in motor neurons: involvement in the pathobiology of ALS mice. Exp. Neurol. 218, 333–346.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Marty, A., and Zimmerberg, J. (1989). Diffusion into the patch-clamp recording pipette of a factor necessary for muscarinic current response. Cell. Signal. 1, 259–268.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Matsuda, W., Furuta, T., Nakamura, K. C., Hioki, H., Fujiyama, F., Arai, R., et al. (2009). Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J. Neurosci. 29, 444–453.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Matthews, E. A., Linardakis, J. M., and Disterhoft, J. F. (2009). The fast and slow afterhyperpolarizations are differentially modulated in hippocampal neurons by aging and learning. J. Neurosci. 29, 4750–4755.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mattiazzi, M., D’Aurelio, M., Gajewski, C. D., Martushova, K., Kiaei, M., Beal, M. F., et al. (2002). Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J. Biol. Chem. 277, 29626–29633.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mattson, M. P. (2007). Calcium and neurodegeneration. Aging Cell 6, 337–350.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mattson, M. P., Rychlik, B., Chu, C., and Christakos, S. (1991). Evidence for calcium-reducing and excito-protective roles for the calcium-binding protein calbindin-D28k in cultured hippocampal neurons. Neuron 6, 41–51.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mayer, M. L., and Westbrook, G. L. (1987). Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurones. J. Physiol. 394, 501–527.

Pubmed Abstract | Pubmed Full Text

McCormack, J. G., and Denton, R. M. (1990). Intracellular calcium ions and intramitochondrial Ca2+ in the regulation of energy metabolism in mammalian tissues. Proc. Nutr. Soc. 49, 57–75.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mellor, J., and Nicoll, R. A. (2001). Hippocampal mossy fiber LTP is independent of postsynaptic calcium. Nat. Neurosci. 4, 125–126.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Michaelis, M. L., Bigelow, D. J., Schoneich, C., Williams, T. D., Ramonda, L., Yin, D., et al. (1996). Decreased plasma membrane calcium transport activity in aging brain. Life Sci. 59, 405–412.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Miljanich, G. P., and Ramachandran, J. (1995). Antagonists of neuronal calcium channels: structure, function, and therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 35, 707–734.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Miller, L. D., Petrozzino, J. J., Golarai, G., and Connor, J. A. (1996). Ca2+ release from intracellular stores induced by afferent stimulation of CA3 pyramidal neurons in hippocampal slices. J. Neurophysiol. 76, 554–562.

Pubmed Abstract | Pubmed Full Text

Mulkey, R. M., and Malenka, R. C. (1992). Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus. Neuron 9, 967–975.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mullany, P., Connolly, S., and Lynch, M. A. (1996). Ageing is associated with changes in glutamate release, protein tyrosine kinase and Ca2+/calmodulin-dependent protein kinase II in rat hippocampus. Eur. J. Pharmacol. 309, 311–315.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Murchison, D., and Griffith, W. H. (1999). Age-related alterations in caffeine-sensitive calcium stores and mitochondrial buffering in rat basal forebrain. Cell Calcium 25, 439–452.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Nakamura, T., Hayashi, H., Satoh, H., Katoh, H., Kaneko, M., and Terada, H. (1999). A single cell model of myocardial reperfusion injury: changes in intracellular Na+ and Ca2+ concentrations in guinea pig ventricular myocytes. Mol. Cell. Biochem. 194, 147–157.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Nakamura, T., Lasser-Ross, N., Nakamura, K., and Ross, W. N. (2002). Spatial segregation and interaction of calcium signalling mechanisms in rat hippocampal CA1 pyramidal neurons. J. Physiol. 543, 465–480.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Nath, S., Goodwin, J., Engelborghs, Y., and Pountney, D. L. (2011). Raised calcium promotes alpha-synuclein aggregate formation. Mol. Cell. Neurosci. 46, 516–526.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Neher, E., and Sakaba, T. (2008). Multiple roles of calcium ions in the regulation of neurotransmitter release. Neuron 59, 861–872.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Nelson, O., Supnet, C., Liu, H., and Bezprozvanny, I. (2010). Familial Alzheimer’s disease mutations in presenilins: effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes. J. Alzheimers Dis. 21, 781–793.

Pubmed Abstract | Pubmed Full Text

Norenberg, M. D., and Rao, K. V. (2007). The mitochondrial permeability transition in neurologic disease. Neurochem. Int. 50, 983–997.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Norris, C. M., Blalock, E. M., Chen, K. C., Porter, N. M., and Landfield, P. W. (2002). Calcineurin enhances L-type Ca(2+) channel activity in hippocampal neurons: increased effect with age in culture. Neuroscience 110, 213–225.

Pubmed Abstract | Pubmed Full Text

Norris, C. M., Korol, D. L., and Foster, T. C. (1996). Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging. J. Neurosci. 16, 5382–5392.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Nowak, L., Bregestovski, P., Ascher, P., Herbet, A., and Prochiantz, A. (1984). Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462–465.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Okado-Matsumoto, A., and Fridovich, I. (2001). Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria. J. Biol. Chem. 276, 38388–38393.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Olivera, B. M., Miljanich, G. P., Ramachandran, J., and Adams, M. E. (1994). Calcium channel diversity and neurotransmitter release: the omega-conotoxins and omega-agatoxins. Annu. Rev. Biochem. 63, 823–867.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Pack-Chung, E., Meyers, M. B., Pettingell, W. P., Moir, R. D., Brownawell, A. M., Cheng, I., et al. (2000). Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor. J. Biol. Chem. 275, 14440–14445.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Parker, I., and Ivorra, I. (1991). Caffeine inhibits inositol trisphosphate-mediated liberation of intracellular calcium in Xenopus oocytes. J. Physiol. 433, 229–240.

Pubmed Abstract | Pubmed Full Text

Pasinelli, P., Belford, M. E., Lennon, N., Bacskai, B. J., Hyman, B. T., Trotti, D., et al. (2004). Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron 43, 19–30.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Patterson, S. L., Grover, L. M., Schwartzkroin, P. A., and Bothwell, M. (1992). Neurotrophin expression in rat hippocampal slices: a stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs. Neuron 9, 1081–1088.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Petrosillo, G., Ruggiero, F. M., Pistolese, M., and Paradies, G. (2004). Ca2+-induced reactive oxygen species production promotes cytochrome c release from rat liver mitochondria via mitochondrial permeability transition (MPT)-dependent and MPT-independent mechanisms: role of cardiolipin. J. Biol. Chem. 279, 53103–53108.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Pilstrom, L., and Kiessling, K. H. (1972). A possible localization of -glycerophosphate dehydrogenase to the inner boundary membrane of mitochondria in livers from rats fed with ethanol. Histochemie 32, 329–334.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ping, H. X., and Shepard, P. D. (1996). Apamin-sensitive Ca(2+)-activated K+ channels regulate pacemaker activity in nigral dopamine neurons. Neuroreport 7, 809–814.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Polans, A. S., Buczylko, J., Crabb, J., and Palczewski, K. (1991). A photoreceptor calcium binding protein is recognized by autoantibodies obtained from patients with cancer-associated retinopathy. J. Cell Biol. 112, 981–989.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Polans, A. S., Witkowska, D., Haley, T. L., Amundson, D., Baizer, L., and Adamus, G. (1995). Recoverin, a photoreceptor-specific calcium-binding protein, is expressed by the tumor of a patient with cancer-associated retinopathy. Proc. Natl. Acad. Sci. U.S.A. 92, 9176–9180.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Poncer, J. C., McKinney, R. A., Gahwiler, B. H., and Thompson, S. M. (1997). Either N- or P-type calcium channels mediate GABA release at distinct hippocampal inhibitory synapses. Neuron 18, 463–472.

CrossRef Full Text

Potier, B., Poindessous-Jazat, F., Dutar, P., and Billard, J. M. (2000). NMDA receptor activation in the aged rat hippocampus. Exp. Gerontol. 35, 1185–1199.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Power, J. M., and Sah, P. (2008). Competition between calcium-activated K+ channels determines cholinergic action on firing properties of basolateral amygdala projection neurons. J. Neurosci. 28, 3209–3220.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Prasad, V., Okunade, G., Liu, L., Paul, R. J., and Shull, G. E. (2007). Distinct phenotypes among plasma membrane Ca2+-ATPase knockout mice. Ann. N. Y. Acad. Sci. 1099, 276–286.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Puopolo, M., Raviola, E., and Bean, B. P. (2007). Roles of subthreshold calcium current and sodium current in spontaneous firing of mouse midbrain dopamine neurons. J. Neurosci. 27, 645–656.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Rahamimoff, R., and Yaari, Y. (1973). Delayed release of transmitter at the frog neuromuscular junction. J. Physiol. 228, 241–257.

Pubmed Abstract | Pubmed Full Text

Ramos-Castaneda, J., Park, Y. N., Liu, M., Hauser, K., Rudolph, H., Shull, G. E., et al. (2005). Deficiency of ATP2C1, a Golgi ion pump, induces secretory pathway defects in endoplasmic reticulum (ER)-associated degradation and sensitivity to ER stress. J. Biol. Chem. 280, 9467–9473.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Reinhardt, T. A., Horst, R. L., and Waters, W. R. (2004). Characterization of Cos-7 cells overexpressing the rat secretory pathway Ca2+-ATPase. Am. J. Physiol. Cell Physiol. 286, C164–C169.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Riascos, D., de Leon, D., Baker-Nigh, A., Nicholas, A., Yukhananov, R., Bu, J., et al. (2011). Age-related loss of calcium buffering and selective neuronal vulnerability in Alzheimer’s disease. Acta Neuropathol. 122, 565–576.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ris, L., and Godaux, E. (2007). Synapse specificity of long-term potentiation breaks down with aging. Learn. Mem. 14, 185–189.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Rizzuto, R., Pinton, P., Brini, M., Chiesa, A., Filippin, L., and Pozzan, T. (1999). Mitochondria as biosensors of calcium microdomains. Cell Calcium 26, 193–199.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Romo, R., and Schultz, W. (1990). Dopamine neurons of the monkey midbrain: contingencies of responses to active touch during self-initiated arm movements. J. Neurophysiol. 63, 592–606.

Pubmed Abstract | Pubmed Full Text

Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A., et al. (1993). Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sabatini, B. L., and Regehr, W. G. (1996). Timing of neurotransmission at fast synapses in the mammalian brain. Nature 384, 170–172.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sagasti, A., Hisamoto, N., Hyodo, J., Tanaka-Hino, M., Matsumoto, K., and Bargmann, C. I. (2001). The CaMKII UNC-43 activates the MAPKKK NSY-1 to execute a lateral signaling decision required for asymmetric olfactory neuron fates. Cell 105, 221–232.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sandin, M., Jasmin, S., and Levere, T. E. (1990). Aging and cognition: facilitation of recent memory in aged nonhuman primates by nimodipine. Neurobiol. Aging 11, 573–575.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Scherer, P. E., Lederkremer, G. Z., Williams, S., Fogliano, M., Baldini, G., and Lodish, H. F. (1996). Cab45, a novel (Ca2+)-binding protein localized to the Golgi lumen. J. Cell Biol. 133, 257–268.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Schinzel, A. C., Takeuchi, O., Huang, Z., Fisher, J. K., Zhou, Z., Rubens, J., et al. (2005). Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc. Natl. Acad. Sci. U.S.A. 102, 12005–12010.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Shankar, S., Teyler, T. J., and Robbins, N. (1998). Aging differentially alters forms of long-term potentiation in rat hippocampal area CA1. J. Neurophysiol. 79, 334–341.

Pubmed Abstract | Pubmed Full Text

Shi, P., Gal, J., Kwinter, D. M., Liu, X., and Zhu, H. (2010). Mitochondrial dysfunction in amyotrophic lateral sclerosis. Biochim. Biophys. Acta 1802, 45–51.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Shinoda, Y., Kamikubo, Y., Egashira, Y., Tominaga-Yoshino, K., and Ogura, A. (2005). Repetition of mGluR-dependent LTD causes slowly developing persistent reduction in synaptic strength accompanied by synapse elimination. Brain Res. 1042, 99–107.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Shtifman, A., Zhong, N., Lopez, J. R., Shen, J., and Xu, J. (2011). Altered Ca2+ homeostasis in the skeletal muscle of DJ-1 null mice. Neurobiol. Aging 32, 125–132.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Shull, G. E. (2000). Gene knockout studies of Ca2+-transporting ATPases. Eur. J. Biochem. 267, 5284–5290.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Silva, A. J., Paylor, R., Wehner, J. M., and Tonegawa, S. (1992a). Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science 257, 206–211.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Silva, A. J., Stevens, C. F., Tonegawa, S., and Wang, Y. (1992b). Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science 257, 201–206.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Silva, A. J., Wang, Y., Paylor, R., Wehner, J. M., Stevens, C. F., and Tonegawa, S. (1992c). Alpha calcium/calmodulin kinase II mutant mice: deficient long-term potentiation and impaired spatial learning. Cold Spring Harb. Symp. Quant. Biol. 57, 527–539.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Siman, R., Noszek, J. C., and Kegerise, C. (1989). Calpain I activation is specifically related to excitatory amino acid induction of hippocampal damage. J. Neurosci. 9, 1579–1590.

Pubmed Abstract | Pubmed Full Text

Snutch, T. P., and Reiner, P. B. (1992). Ca2+ channels: diversity of form and function. Curr. Opin. Neurobiol. 2, 247–253.

CrossRef Full Text

Sokal, I., Li, N., Surgucheva, I., Warren, M. J., Payne, A. M., Bhattacharya, S. S., et al. (1998). GCAP1 (Y99C) mutant is constitutively active in autosomal dominant cone dystrophy. Mol. Cell. 2, 129–133.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sokal, I., Li, N., Verlinde, C. L., Haeseleer, F., Baehr, W., and Palczewski, K. (2000). Ca(2+)-binding proteins in the retina: from discovery to etiology of human disease(1). Biochim. Biophys. Acta 1498, 233–251.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sollner, T., Whiteheart, S. W., Brunner, M., Erdjument-Bromage, H., Geromanos, S., Tempst, P., et al. (1993). SNAP receptors implicated in vesicle targeting and fusion. Nature 362, 318–324.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Stanley, E. F. (1993). Presynaptic calcium channels and the transmitter release mechanism. Ann. N. Y. Acad. Sci. 681, 368–372.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Strehler, E. E., Filoteo, A. G., Penniston, J. T., and Caride, A. J. (2007). Plasma-membrane Ca(2+) pumps: structural diversity as the basis for functional versatility. Biochem. Soc. Trans. 35, 919–922.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Strehler, E. E., and Treiman, M. (2004). Calcium pumps of plasma membrane and cell interior. Curr. Mol. Med. 4, 323–335.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Striessnig, J., Koschak, A., Sinnegger-Brauns, M. J., Hetzenauer, A., Nguyen, N. K., Busquet, P., et al. (2006). Role of voltage-gated L-type Ca2+ channel isoforms for brain function. Biochem. Soc. Trans. 34, 903–909.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sudbrak, R., Brown, J., Dobson-Stone, C., Carter, S., Ramser, J., White, J., et al. (2000). Hailey–Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump. Hum. Mol. Genet. 9, 1131–1140.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sudhof, T. C. (1995). The synaptic vesicle cycle: a cascade of protein–protein interactions. Nature 375, 645–653.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sudhof, T. C. (2004). The synaptic vesicle cycle. Annu. Rev. Neurosci. 27, 509–547.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Szekely, A. M., Costa, E., and Grayson, D. R. (1990). Transcriptional program coordination by N-methyl-D-aspartate-sensitive glutamate receptor stimulation in primary cultures of cerebellar neurons. Mol. Pharmacol. 38, 624–633.

Pubmed Abstract | Pubmed Full Text

Tachikui, H., Navet, A. F., and Ozawa, M. (1997). Identification of the Ca(2+)-binding domains in reticulocalbin, an endoplasmic reticulum resident Ca(2+)-binding protein with multiple EF-hand motifs. J. Biochem. 121, 145–149.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Taira, T., Saito, Y., Niki, T., Iguchi-Ariga, S. M., Takahashi, K., and Ariga, H. (2004). DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep. 5, 213–218.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Takahashi, M., and Catterall, W. A. (1987). Identification of an alpha subunit of dihydropyridine-sensitive brain calcium channels. Science 236, 88–91.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tao, X., Finkbeiner, S., Arnold, D. B., Shaywitz, A. J., and Greenberg, M. E. (1998). Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20, 709–726.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tapia-Arancibia, L., Aliaga, E., Silhol, M., and Arancibia, S. (2008). New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Res. Rev. 59, 201–220.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Thibault, O., Gant, J. C., and Landfield, P. W. (2007). Expansion of the calcium hypothesis of brain aging and Alzheimer’s disease: minding the store. Aging Cell 6, 307–317.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Thibault, O., and Landfield, P. W. (1996). Increase in single L-type calcium channels in hippocampal neurons during aging. Science 272, 1017–1020.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Toescu, E. C., and Verkhratsky, A. (2004). Ca2+ and mitochondria as substrates for deficits in synaptic plasticity in normal brain ageing. J. Cell Mol. Med. 8, 181–190.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Toescu, E. C., and Vreugdenhil, M. (2010). Calcium and normal brain ageing. Cell Calcium 47, 158–164.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tokuyama, W., Okuno, H., Hashimoto, T., Xin Li, Y., and Miyashita, Y. (2000). BDNF upregulation during declarative memory formation in monkey inferior temporal cortex. Nat. Neurosci. 3, 1134–1142.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tollefson, G. D. (1990). Short-term effects of the calcium channel blocker nimodipine (Bay-e-9736) in the management of primary degenerative dementia. Biol. Psychiatry 27, 1133–1142.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tonkikh, A., Janus, C., El-Beheiry, H., Pennefather, P. S., Samoilova, M., McDonald, P., et al. (2006). Calcium chelation improves spatial learning and synaptic plasticity in aged rats. Exp. Neurol. 197, 291–300.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tonkikh, A. A., and Carlen, P. L. (2009). Impaired presynaptic cytosolic and mitochondrial calcium dynamics in aged compared to young adult hippocampal CA1 synapses ameliorated by calcium chelation. Neuroscience 159, 1300–1308.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tsien, R. W., Ellinor, P. T., and Horne, W. A. (1991). Molecular diversity of voltage-dependent Ca2+ channels. Trends Pharmacol. Sci. 12, 349–354.

CrossRef Full Text

Tsien, R. W., Lipscombe, D., Madison, D. V., Bley, K. R., and Fox, A. P. (1988). Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci. 11, 431–438.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tsuboi, K., Kimber, T. A., and Shults, C. W. (2000). Calretinin-containing axons and neurons are resistant to an intrastriatal 6-hydroxydopamine lesion. Brain Res. 866, 55–64.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Urushitani, M., Sik, A., Sakurai, T., Nukina, N., Takahashi, R., and Julien, J. P. (2006). Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat. Neurosci. 9, 108–118.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Van Baelen, K., Vanoevelen, J., Callewaert, G., Parys, J. B., De Smedt, H., Raeymaekers, L., et al. (2003). The contribution of the SPCA1 Ca2+ pump to the Ca2+ accumulation in the Golgi apparatus of HeLa cells assessed via RNA-mediated interference. Biochem. Biophys. Res. Commun. 306, 430–436.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Van Brederode, J. F., Mulligan, K. A., and Hendrickson, A. E. (1990). Calcium-binding proteins as markers for subpopulations of GABAergic neurons in monkey striate cortex. J. Comp. Neurol. 298, 1–22.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Vande Velde, C., Miller, T. M., Cashman, N. R., and Cleveland, D. W. (2008). Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc. Natl. Acad. Sci. U.S.A. 105, 4022–4027.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Vanoevelen, J., Dode, L., Van Baelen, K., Fairclough, R. J., Missiaen, L., Raeymaekers, L., et al. (2005). The secretory pathway Ca2+/Mn2+-ATPase 2 is a Golgi-localized pump with high affinity for Ca2+ ions. J. Biol. Chem. 280, 22800–22808.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Vercesi, A. E., Kowaltowski, A. J., Grijalba, M. T., Meinicke, A. R., and Castilho, R. F. (1997). The role of reactive oxygen species in mitochondrial permeability transition. Biosci. Rep. 17, 43–52.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Vijayvergiya, C., Beal, M. F., Buck, J., and Manfredi, G. (2005). Mutant superoxide dismutase 1 forms aggregates in the brain mitochondrial matrix of amyotrophic lateral sclerosis mice. J. Neurosci. 25, 2463–2470.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Vouimba, R. M., Foy, M. R., Foy, J. G., and Thompson, R. F. (2000). 17beta-estradiol suppresses expression of long-term depression in aged rats. Brain Res. Bull. 53, 783–787.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wei, Y. H. (1998). Oxidative stress and mitochondrial DNA mutations in human aging. Proc. Soc. Exp. Biol. Med. 217, 53–63.

Pubmed Abstract | Pubmed Full Text

Werth, J. L., Usachev, Y. M., and Thayer, S. A. (1996). Modulation of calcium efflux from cultured rat dorsal root ganglion neurons. J. Neurosci. 16, 1008–1015.

CrossRef Full Text

West, A. E., Chen, W. G., Dalva, M. B., Dolmetsch, R. E., Kornhauser, J. M., Shaywitz, A. J., et al. (2001). Calcium regulation of neuronal gene expression. Proc. Natl. Acad. Sci. U.S.A. 98, 11024–11031.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wilson, C. J., and Callaway, J. C. (2000). Coupled oscillator model of the dopaminergic neuron of the substantia nigra. J. Neurophysiol. 83, 3084–3100.

Pubmed Abstract | Pubmed Full Text

Wood-Kaczmar, A., Gandhi, S., Yao, Z., Abramov, A. Y., Miljan, E. A., Keen, G., et al. (2008). PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE 3, e2455. doi: 10.1371/journal.pone.0002455

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Xiang, M., Mohamalawari, D., and Rao, R. (2005). A novel isoform of the secretory pathway Ca2+,Mn(2+)-ATPase, hSPCA2, has unusual properties and is expressed in the brain. J. Biol. Chem. 280, 11608–11614.

Pubmed Abstract | Pubmed Full Text

Xiong, J., Verkhratsky, A., and Toescu, E. C. (2002). Changes in mitochondrial status associated with altered Ca2+ homeostasis in aged cerebellar granule neurons in brain slices. J. Neurosci. 22, 10761–10771.

Pubmed Abstract | Pubmed Full Text

Yamada, T., McGeer, P. L., Baimbridge, K. G., and McGeer, E. G. (1990). Relative sparing in Parkinson’s disease of substantia nigra dopamine neurons containing calbindin-D28K. Brain Res. 526, 303–307.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Yeckel, M. F., Kapur, A., and Johnston, D. (1999). Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism. Nat. Neurosci. 2, 625–633.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Yoo, A. S., Cheng, I., Chung, S., Grenfell, T. Z., Lee, H., Pack-Chung, E., et al. (2000). Presenilin-mediated modulation of capacitative calcium entry. Neuron 27, 561–572.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Zeng, Y., Tan, M., Kohyama, J., Sneddon, M., Watson, J. B., Sun, Y. E., et al. (2011). Epigenetic enhancement of BDNF signaling rescues synaptic plasticity in aging. J. Neurosci. 31, 17800–17810.

Pubmed Abstract | Pubmed Full Text

Zhou, Q., Homma, K. J., and Poo, M. M. (2004). Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44, 749–757.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Keywords: endoplasmic reticulum, Golgi, long-term potentiation, ion channel, mitochondria, neurodegeneration, neurotransmitter, synaptic plasticity

Citation: Nikoletopoulou V and Tavernarakis N (2012) Calcium homeostasis in aging neurons. Front. Gene. 3:200. doi:10.3389/fgene.2012.00200

Received: 22 May 2012; Paper pending published: 04 July 2012;
Accepted: 19 September 2012; Published online: 02 October 2012.

Edited by:

Joy Alcedo, Wayne State University, USA

Reviewed by:

Joy Alcedo, Wayne State University, USA
QueeLim Ch’Ng, King’s College London, UK

Copyright: © 2012 Nikoletopoulou and Tavernarakis. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

*Correspondence: Nektarios Tavernarakis, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology – Hellas, Vassilika Vouton, PO Box 1385, Heraklion 71110, Crete, Greece. e-mail: tavernarakis@imbb.forth.gr