Organelle-Specific Sensors for Monitoring Ca²⁺ Dynamics in Neurons

Abstract

Calcium (Ca²⁺) plays innumerable critical functions in neurons ranging from regulation of neurotransmitter release and synaptic plasticity to activity-dependent transcription. Therefore, more than any other cell types, neurons are critically dependent on spatially and temporally controlled Ca²⁺ dynamics. This is achieved through an exquisite level of compartmentalization of Ca²⁺ storage and release from various organelles. The function of these organelles in the regulation of Ca²⁺ dynamics has been studied for decades using electrophysiological and optical methods combined with pharmacological and genetic alterations. Mitochondria and the endoplasmic reticulum (ER) are among the organelles playing the most critical roles in Ca²⁺ dynamics in neurons. At presynaptic boutons, Ca²⁺ triggers neurotransmitter release and synaptic plasticity, and postsynaptically, Ca²⁺ mobilization mediates long-term synaptic plasticity. To explore Ca²⁺ dynamics in live cells and intact animals, various synthetic and genetically encoded fluorescent Ca²⁺ sensors were developed, and recently, many groups actively increased the sensitivity and diversity of genetically encoded Ca²⁺ indicators (GECIs). Following conjugation with various signal peptides, these improved GECIs can be targeted to specific subcellular compartments, allowing monitoring of organelle-specific Ca²⁺ dynamics. Here, we review recent findings unraveling novel roles for mitochondria- and ER-dependent Ca²⁺ dynamics in neurons and at synapses.

Introduction

Calcium (Ca²⁺) ions govern prevalent physiological processes in various cell types (Rizzuto and Pozzan, 2006; Clapham, 2007). This is especially prominent in excitable cells like neurons where Ca²⁺ influx through the plasma membrane and release of Ca²⁺ from internal stores transduce the effects of changes in membrane polarization and therefore mediate faithful transfer or storage of information over various timescales (milliseconds to minutes/hours). Therefore, regulation of intracellular Ca²⁺ homeostasis is central to the proper function of neuronal circuits. The maintenance of baseline levels of intracellular Ca²⁺ levels is regulated in part through exchangers and pumps such as the plasma membrane Ca²⁺-ATPase (PMCA pump), the Na⁺/Ca²⁺ exchanger (NCX), and the Na⁺/Ca²⁺-K⁺ exchanger (NCKX) which extrude Ca²⁺ through the plasma membrane into the extracellular space. In addition to these mechanisms, intracellular organelles, such as mitochondria and endoplasmic reticulum (ER), are able to regulate cytoplasmic Ca²⁺ ([Ca²⁺]_c) through mitochondrial calcium uniporter (MCU) and smooth endoplasmic reticulum Ca²⁺-ATPase (SERCA), respectively.

In neurons, mitochondria and ER play important physiological roles via [Ca²⁺]_c regulation, thereby diverse synaptic functions including basal synaptic transmission, presynaptic short-term plasticity, and long-term plasticity can be regulated by these organelles (Verkhratsky, 2005; Bardo et al., 2006; Mattson et al., 2008; Vos et al., 2010). In addition, impaired Ca²⁺ homeostasis in the nervous system has been proposed to play an important function in the physio-pathological mechanisms underlying Alzheimer’s disease, Parkinson’s disease, and spinocerebellar ataxia (Verkhratsky, 2005; Mattson et al., 2008; Schon and Przedborski, 2011).

To monitor Ca²⁺ dynamics, various fluorescent Ca²⁺ dyes and genetically encoded Ca²⁺ indicators (GECIs) were developed and applied both in vitro and in vivo. Also, GECIs tagged with target peptide sequences have allowed imaging of Ca²⁺ dynamics in specific organelles (Rizzuto et al., 1992; Palmer et al., 2004; Palmer and Tsien, 2006).

Previously published reviews have already summarized the usefulness and limitations of various Ca²⁺ sensors and GECIs applied to neuronal and non-neuronal cells (Palmer and Tsien, 2006; Knopfel, 2012; Tian et al., 2012; Rose et al., 2014). In this review, we only describe recently uncovered insights about Ca²⁺ dynamics and its regulation by mitochondria and ER, and we discuss how these organelle-specific Ca²⁺ sensors have been used for the exploration of the role of these subcellular compartments in the regulation of Ca²⁺ homeostasis and synaptic function in neurons.

Unveiled Synaptic Functions of Mitochondria-Dependent Ca²⁺ Homeostasis

Mitochondrial Ca²⁺ uptake has been studied since the 1950s from studies of rat heart muscle and kidney (Slater and Cleland, 1953; Deluca and Engstrom, 1961). In the nervous system, mitochondria were described at presynaptic terminals and dendrites of various neuronal subtypes using the light and electron microscope (EM) several decades ago (Bartelmez and Hoerr, 1933; Palay, 1956; Gray, 1963; Shepherd and Harris, 1998; Rowland et al., 2000). In axons, mitochondria are short and sparsely distributed, and interestingly, several studies showed that half of presynaptic boutons are occupied by mitochondria (Shepherd and Harris, 1998; Kang et al., 2008). In contrast, dendritic mitochondria have tubular shapes and they are rarely observed in postsynaptic spines in the excitatory neurons (Sheng and Hoogenraad, 2007; Kasthuri et al., 2015).

At presynaptic boutons and terminals, synaptic vesicle (SV) fusion with the plasma membrane occurs following increase of [Ca²⁺]_c following opening of voltage-sensitive Ca²⁺ channels (VSCC) followed by Ca²⁺ binding to sensors like synaptotagmins (Schneggenburger and Neher, 2005; Neher and Sakaba, 2008; Jahn and Fasshauer, 2012; Südhof, 2012). The ability of mitochondria to import Ca²⁺ into the mitochondrial matrix ([Ca²⁺]_m) plays a role in regulating presynaptic [Ca²⁺]_c. This has been characterized in various species, neuronal cell types and circuits (Figure 1A). At the Drosophila neuromuscular junction (NMJ), the GTPase dMiro mutant lacks presynaptic mitochondria through impaired axonal transport (Guo et al., 2005; Wang and Schwarz, 2009). During prolonged stimulation, these mutants lacking presynaptic mitochondria displayed subtle, but significantly increased presynaptic Ca²⁺ accumulation and display decrease forms of sustained synaptic transmission or synaptic “fatigue” (Guo et al., 2005). Drosophila Drp1 mutants also deplete presynaptic mitochondria at NMJ and exhibit elevated presynaptic Ca²⁺ levels in resting and evoked states. However, spontaneous release (mini Excitatory junctional potential, mEJP) was not altered, but the evoked synaptic transmission was impaired during high frequency stimulation, and this defect was partially rescued by ATP (Verstreken et al., 2005) suggesting that mitochondria plays a role in synaptic transmission through their ability to generate ATP through oxidative phosphorylation. Although mitochondrial Ca²⁺ uptake has limited effects on Drosophila NMJ neurons, in mammalian NMJ terminals, acute inhibition of mitochondrial Ca²⁺ uptake causes rapid depression of the endplate potential (EPP) and increased asynchronous release (David and Barrett, 2003). Furthermore, in synapses of the mammalian central nervous system (CNS), mitochondria-dependent Ca²⁺ uptake accelerates the recovery from synaptic depression in the calyx of Held (Billups and Forsythe, 2002). Other studies in mammalian hippocampal neurons claimed that impaired mitochondrial anchoring at presynaptic sites increases presynaptic Ca²⁺ during repetitive stimulation and produces short-term facilitation (STF), and insulin-like growth factor-1 receptor (IGF-1R) signaling regulates resting mitochondrial Ca²⁺ level and spontaneous transmission (Kang et al., 2008; Gazit et al., 2016). Although most pharmacological studies employed uncoupling agents as mitochondrial Ca²⁺ influx blocker, which may affect ATP production, these reports support presynaptic control via mitochondrial Ca²⁺ import (Ly and Verstreken, 2006). A recent study demonstrates that presynaptic boutons associated with mitochondria display lower levels of [Ca²⁺]_c accumulation than presynaptic boutons not associated with mitochondria (Kwon et al., 2016). Furthermore, acute inhibition of mitochondria calcium import increased [Ca²⁺]_c accumulation at presynaptic boutons occupied by mitochondria. In the same study, we demonstrate that this mitochondria-dependent regulation of [Ca²⁺]_c plays an important role in regulating presynaptic release properties including spontaneous release, asynchronous release and short-term synaptic plasticity.

Figure 1

In addition to regulation of [Ca²⁺]_c clearance, Ca²⁺ release from mitochondria plays important roles at presynaptic sites (Figure 1A). Following the sustained high frequency stimulation, an enhancement of synaptic transmission lasting tens of seconds to minutes is observed and which is called post-tetanic potentiation (PTP; Zucker, 1989). Mitochondrial Ca²⁺ release is suggested as one of the underlying mechanisms for this prolonged enhancement of synaptic transmission. Pharmacological inhibition of mitochondrial Ca²⁺ uptake and release at the crayfish NMJ impaired PTP (Tang and Zucker, 1997; Zhong et al., 2001). Furthermore, similar phenotypes were observed at mouse NMJ and hippocampal mossy fiber synapses with blocking the mitochondrial NCX, which mediates mitochondrial Ca²⁺ release (García-Chacón et al., 2006; Lee et al., 2007).

In contrast to presynaptic boutons and terminals, the postsynaptic function of mitochondrial Ca²⁺ regulation is less well-documented. In mouse hippocampal pyramidal neurons (Li et al., 2004), a minority (<5%) of dendritic spines contains mitochondria. Also, large branched spines in hippocampal CA3 contain mitochondria (Chicurel and Harris, 1992). However, a physiological role of these postsynaptic mitochondria is largely unknown. In general, mitochondria are distributed primarily in dendrite shaft and therefore localized microns away from the postsynaptic density, but might still be able to buffer [Ca²⁺]_c mobilized through Ca²⁺-channels and glutamate receptors (Thayer and Miller, 1990; White and Reynolds, 1995; Wang and Thayer, 2002). This mitochondrial calcium import can stimulate tricarboxylic acid (TCA) cycle and might increase ATP production (Kann and Kovács, 2007) and may also regulate other ATP-dependent Ca²⁺ pumps like PMCA and SERCA. While it is still unclear whether or not mitochondria play significant roles in regulating postsynaptic [Ca²⁺]_c under physiological conditions of neurotransmission, they might play a role in pathophysiological contexts. For example, neurons lacking LRRK2, a protein associated with Parkinson’s disease, show impaired dendritic Ca²⁺ homeostasis through mitochondrial defects and thought to cause defective mitochondrial depolarization and reduction in dendritic complexity (Figure 1B; Cherra et al., 2013).

Overall, mitochondria-dependent Ca²⁺ clearance and release in neurons plays important physiological and developmental roles pre- and post-synaptically but their functional importance seems to depend on the neuronal subtypes and the structure/size of the pre- and postsynaptic compartments.

Mitochondrial Ca²⁺-Imaging in Neurons and at Synapses

To investigate organelle-specific Ca²⁺ dynamics, various Ca²⁺ sensors are developed (Table 1). One of the first method developed to monitor mitochondrial Ca²⁺ dynamics was established using rhod-2, a cationic chemical Ca²⁺-binding fluorophore preferentially accumulating in the mitochondrial matrix presumably because of the highly negative membrane potential across the mitochondrial inner membrane (Minta et al., 1989). Then, in the calyx of Held, rhod-2 and rhod-FF (low affinity version) were used to visualize presynaptic mitochondrial Ca²⁺ transient (Billups and Forsythe, 2002). However, these dyes cannot be precisely targeted to these organelles. Therefore, GECIs have recently become the preferred method to image Ca²⁺ in specific organelles including mitochondria. For mitochondrial matrix localization, the targeting presequence of subunit VIII of human cytochrome c oxidase (COXVIII) was tagged to GECIs (Rizzuto et al., 1992). Mitochondria-targeted aequorin (mt-AEQ), a luminescent Ca²⁺ indicator, was first employed to monitor the neuronal mitochondrial Ca²⁺, and this probe showed NMDA-induced mitochondrial Ca²⁺ increase in hippocampal neurons (Baron et al., 2003). However, this probe needs a chemical reaction characterized by a modest turnover rate and has very limited dynamic range (Palmer and Tsien, 2006). Other GECIs have been developed and tested in various neuronal subtypes with the same targeting sequence. Mitochondrial-targeted ratiometric pericam (2mtRP) consists of circularly permutated Enhanced yellow fluorescent protein (cpEFYP) conjugated with Ca²⁺-responsive calmodulin (CaM) and its binding peptide (Nagai et al., 2001; Robert et al., 2001). This probe has a bimodal excitation spectrum and the relative emission intensity is dependent on Ca²⁺-binding. In hippocampal neurons, the use of 2mtRP described mitochondrial Ca²⁺ uptake and also determined cytosolic Ca²⁺ rise upon synaptic activation via dual imaging with cytosolic Ca²⁺ dye (fura-red AM; Young et al., 2008). Other CaM conjugated cpEGFPs called GCaMPs (mito-GCaMP2, 2mtGCaMP6m, and mito-GCaMP5G) were used to monitor axonal mitochondrial Ca²⁺ (Gazit et al., 2016; Kwon et al., 2016; Marland et al., 2016). Both sensors displayed action potential (AP)-dependent mitochondrial Ca²⁺ import. In addition, red fluorescent GECIs by replacing cpEGFP with cpmApple or cpmRuby (mtRCaMP1e and LAR-GECO1.2) revealed mitochondrial Ca²⁺ import simultaneously with cytosolic Ca²⁺ (Akerboom et al., 2013; Wu et al., 2014).

However, these fluorescent proteins have some limitations, for example, they are affected by pH and mitochondrial matrix pH (pH_m) can be changed by Ca²⁺ influx (Abad et al., 2004; Poburko et al., 2011; Chouhan et al., 2012; Marland et al., 2016). In addition to this point, [Ca²⁺]_m can span broad ranges (0.05–300 μM) depending on cell types and stimulation protocol (Arnaudeau et al., 2001; Palmer and Tsien, 2006). Thus, K_d value for Ca²⁺ of mitochondrial GECI should be considered for experimental purposes because high affinity (low K_d) sensors can be easily saturated by high [Ca²⁺]_m and low affinity (high K_d) sensors may not be sensitive enough to detect small [Ca²⁺]_m changes. Several studies reported low affinity mitochondrial Ca²⁺ probes for avoiding saturation (Arnaudeau et al., 2001; Suzuki et al., 2014).

In conclusion, these mitochondria-targeted GECIs allow imaging of mitochondria Ca²⁺ dynamics in neurons and have revealed interesting, synapse-specific properties of mitochondria in the regulation of [Ca²⁺]_c and neurotransmitter release properties.

Regulation of Synaptic Ca²⁺ Dynamics by the Endoplasmic Reticulum

Neurons are among the most polarized cell types in our body and consists of a soma, relatively short dendrites and long axons. ER is found throughout the entire length of neuronal processes, and usually rough ER is prominent in the cell body and proximal dendrites, whereas smooth ER is dominant in distal dendrites, spines and axons (Spacek and Harris, 1997; Verkhratsky, 2005). ER imports and sequesters large amount of Ca²⁺ ([Ca²⁺]_er ~500 μM) through SERCA and store-operated Ca²⁺ entry (SOCE) mechanism (Verkhratsky, 2005; Bardo et al., 2006). Ca²⁺ release from ER is mediated by two major mechanisms, called Ca²⁺-induced Ca²⁺ release (CICR) and IP₃-induced Ca²⁺ release (IICR; Verkhratsky, 2005; Bardo et al., 2006). CICR is caused by the cytosolic Ca²⁺ increase through N-Methyl-D-Aspartate receptors (NMDAR, GluN receptors) and voltage-gated Ca²⁺ channels (VGCCs), whereas IICR is triggered by IP₃, which is generated via activation of phospholipase C (PLC) depending on metabotropic glutamate receptors (mGluRs) or other receptors like receptor tyrosine kinases (Figure 1).

Ryanodine receptors (RyRs) are involved in CICR, and they have three major subtypes; RyR1, RyR2, and RyR3. All of these isoforms are detected in the brain, and show region-specific expression (Sharp et al., 1993; Furuichi et al., 1994; Giannini et al., 1995; Verkhratsky, 2005; Bardo et al., 2006; Baker et al., 2013). Similar to RyRs, IP₃ receptor (IP₃R), which mediate IICR, consist of three isoforms, IP₃R1, IP₃R2, and IP₃R3, but IP₃R1 is the dominant form in the brain (Sharp et al., 1993, 1999; Verkhratsky, 2005; Bardo et al., 2006; Baker et al., 2013).

Long-term synaptic plasticity is regulated by Ca²⁺-dependent signaling mechanisms such as Ca²⁺/calmodulin-dependent kinase II (CaMKII), calcineurin (a Ca²⁺-dependent phosphatase), protein phosphatase 1 (PP1) and protein kinase C (PKC; Malenka and Nicoll, 1999; Yang et al., 1999; Lüscher and Malenka, 2012). Therefore, Ca²⁺ release from intracellular stores like the ER regulates long-term synaptic plasticity in specific circuits.

In cerebellar Purkinje cell dendrites, mGluR-IP₃-dependent Ca²⁺ increase is observed during parallel fiber (PF) stimulation and this mediates long-term depression (LTD) of PF-Purkinje cell pathway (Finch and Augustine, 1998; Takechi et al., 1998; Miyata et al., 2000; Wang et al., 2000). At synapses made by hippocampal Schaffer collateral (SC) onto CA1 pyramidal neurons, both long-term potentiation (LTP) and LTD are linked to IP₃-dependent signaling (Oliet et al., 1997; Nishiyama et al., 2000; Raymond and Redman, 2002; Nagase et al., 2003). In addition, CICR is also observed in CA1 pyramidal neuronal spines, and LTD is abolished in RyR3-deficient mice and following application of RyR inhibitor (ryanodine) although the connection between CICR and LTP is controversial in SC-CA1 pathway (Reyes and Stanton, 1996; Emptage et al., 1999; Futatsugi et al., 1999; Sandler and Barbara, 1999; Kovalchuk et al., 2000; Nishiyama et al., 2000; Raymond and Redman, 2002). Hippocampal mossy fiber pathway (MF, dentate gyrus to CA3) shows IICR- and CICR-dependent LTP and LTD, however, there are conflicting results regarding the underlying mechanisms (Figure 1B; Yeckel et al., 1999; Itoh et al., 2001; Kapur et al., 2001; Mellor and Nicoll, 2001; Lauri et al., 2003; Lei et al., 2003).

Presynaptic ER-dependent Ca²⁺ release is also detected and contributes to changes in neurotransmitter release properties and short-term synaptic plasticity at various inhibitory and excitatory synapses including basket cell to Purkinje cell synapses, hippocampal MF pathway, SC-CA1 and CA3-CA3 pyramidal neuron synapses (Figure 1A; Llano et al., 2000; Emptage et al., 2001; Liang et al., 2002; Galante and Marty, 2003; Lauri et al., 2003; Sharma and Vijayaraghavan, 2003; Unni et al., 2004; Mathew and Hablitz, 2008).

In addition to Ca²⁺ efflux, Ca²⁺ uptake by ER via SERCA pump affects STF at SC-CA1 presynapses and NMJ (Figure 1A; Castonguay and Robitaille, 2001; Scullin and Partridge, 2010; Scullin et al., 2010). Stromal interaction molecules (STIMs) and Orai1, which allow SOCE, are localized to neuronal compartment including dendritic spines, and impaired SOCE alters α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, neuronal Ca²⁺ signaling and LTP in CA1 pyramidal neuron and cerebellar Purkinje neurons (Baba et al., 2003; Hartmann et al., 2014; Korkotian et al., 2014; Garcia-Alvarez et al., 2015; Segal and Korkotian, 2015).

Imaging Neuronal ER Ca²⁺ Dynamics

As mentioned above, ER contains high levels of Ca²⁺, therefore, in order to monitor Ca²⁺ dynamics in the ER lumen, low affinity sensors were employed. Mag-Fura-2, a low affinity membrane-permeable dye (K_d = 53 μM), has been the first applied for neuronal ER Ca²⁺ measurement, and after loading this dye in the cytoplasm and organelles, cytosolic dye was removed by perfusion with dye-free pipette solution (Solovyova et al., 2002). This allowed for the first time the visualization of caffeine-induced Ca²⁺ release and reuptake in the ER of dorsal root ganglia (DRG) neurons (Table 1).

However, this method can non-specifically label internal compartments, therefore, genetically targeted sensors have been developed more recently for the visualization of ER-derived Ca²⁺ dynamics (Table 1). The signal sequence of calreticulin, a Ca²⁺-binding protein in ER, and an ER retention sequence, KDEL, lead GECIs into the ER lumen, and to optimize for measuring a massive amount of [Ca²⁺]_er, various mutations were applied to the CaM domain or EF-hand motif of existing GECIs for reducing their Ca²⁺ affinity. A fluorescence resonance energy transfer (FRET)-based Ca²⁺ sensor, D1ER, showed altered ER Ca²⁺ leak function in hippocampal neurons of presenilin double knockout and Alzheimer’s disease model mice (Zhang et al., 2010). Also, bioluminescence-based sensor, GFP-Aequorin protein (GAP), was modified and targeted to ER of DRG and hippocampal neurons, and showed 3- to 4-fold larger ratio change than D1ER (Rodriguez-Garcia et al., 2014). In addition, recently established GCaMP variants for ER Ca²⁺ detection, calcium-measuring organelle-entrapped protein indicator one in the ER (CEPIA1er) and GCaMPer (10.19), characterized ER Ca²⁺ uptake and release in cortical neurons and cerebellar Purkinje cells (Suzuki et al., 2014; Henderson et al., 2015). Interestingly, cerebellar Purkinje cells displayed differential ER Ca²⁺ dynamics in postsynaptic compartment depending on the nature of synaptic inputs (Okubo et al., 2015). These lumenal ER Ca²⁺ indicators also revealed interesting dynamics in dendritic spines, which suggest that [Ca²⁺]_er and therefore [Ca²⁺]_c can undergo synapse-specific regulation (Suzuki et al., 2014; Henderson et al., 2015).

Future Perspectives

Recent studies characterized the roles of presynaptic mitochondria and circuit-specific ER Ca²⁺ mobility in dendrites directly via live imaging (Okubo et al., 2015; Kwon et al., 2016), however, organelle-specific Ca²⁺ dynamics at local synapses is only beginning to be explored. Genetically-encoded Ca²⁺ sensors targeted to intracellular organelle and/or to specific synapses as well as functional indicators (like pHluorin-tagged synaptophysin or GluRs) will lead to the identification of synapse- and circuit-specific roles of mitochondria and ER Ca²⁺ in neurons.

MCU has been recently shown to be associated with multiple regulatory proteins, which seems to modify or gate its gating properties and can prevent or enhance mitochondrial Ca²⁺ uptake upon changes in cytosolic Ca²⁺ dynamics (Perocchi et al., 2010; Mallilankaraman et al., 2012; Csordás et al., 2013; Plovanich et al., 2013; Raffaello et al., 2013; Sancak et al., 2013; De Stefani et al., 2015). In addition, MCU activity can be differentially controlled in different tissues (Fieni et al., 2012). Therefore, future investigations should probe the function of this MCU-regulatory complex in neurons and test if MCU and/or MCU-associated proteins can act as neuronal subtype-specific and/or synapse-specific functional modifiers.

In non-neuronal cells, ER and mitochondria establish focal connections which play a key role in Ca²⁺ transfer from ER to mitochondria which has been characterized via intra- and inter-organelle Ca²⁺ imaging (Rizzuto et al., 1993, 2012; Csordás et al., 2010; Kornmann, 2013). This transfer modulates ATP production in mitochondria and may also affect lipid exchange between these two organelles (Voelker, 1990; Cárdenas et al., 2010; Fujimoto and Hayashi, 2011). At present, in neurons, the role of Ca²⁺ translocation between ER and mitochondria is largely unknown. Although immuno-EM images in vivo and Ca²⁺ imaging with dyes in respiratory motor neurons suggested ER-mitochondria Ca²⁺ crosstalk, future work will need to establish the context in which ER-mitochondria interface regulates Ca²⁺ dynamics and synaptic function (Takei et al., 1992; Shoshan-Barmatz et al., 2004; Mironov and Symonchuk, 2006).

Funding

This work was partially funded by support from the NIH-NINDS (R01NS067557, FP), Japan society for the promotion of science fellowship for research abroad and The Uehara Memorial Foundation (YH), and a grant from the Human Frontier Science Program long-term fellowship (S-KK).

References

• 1

  AbadM. F.Di BenedettoG.MagalhãesP. J.FilippinL.PozzanT. (2004). Mitochondrial pH monitored by a new engineered green fluorescent protein mutant. J. Biol. Chem.279, 11521–11529. 10.1074/jbc.m306766200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  AkerboomJ.Carreras CalderónN.TianL.WabnigS.PriggeM.TolöJ.et al. (2013). Genetically encoded calcium indicators for multi-color neural activity imaging and combination with optogenetics. Front. Mol. Neurosci.6:2. 10.3389/fnmol.2013.00002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  ArnaudeauS.KelleyW. L.WalshJ. V.Jr.DemaurexN. (2001). Mitochondria recycle Ca²⁺ to the endoplasmic reticulum and prevent the depletion of neighboring endoplasmic reticulum regions. J. Biol. Chem.276, 29430–29439. 10.1074/jbc.m103274200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  BabaA.YasuiT.FujisawaS.YamadaR. X.YamadaM. K.NishiyamaN.et al. (2003). Activity-evoked capacitative Ca²⁺ entry: implications in synaptic plasticity. J. Neurosci.23, 7737–7741.

  • Pubmed Abstract
  • Google Scholar

• 5

  BakerK. D.EdwardsT. M.RickardN. S. (2013). The role of intracellular calcium stores in synaptic plasticity and memory consolidation. Neurosci. Biobehav. Rev.37, 1211–1239. 10.1016/j.neubiorev.2013.04.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6

  BardoS.CavazziniM. G.EmptageN. (2006). The role of the endoplasmic reticulum Ca²⁺ store in the plasticity of central neurons. Trends Pharmacol. Sci.27, 78–84. 10.1016/j.tips.2005.12.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7

  BaronK. T.WangG. J.PaduaR. A.CampbellC.ThayerS. A. (2003). NMDA-evoked consumption and recovery of mitochondrially targeted aequorin suggests increased Ca²⁺ uptake by a subset of mitochondria in hippocampal neurons. Brain Res.993, 124–132. 10.1016/j.brainres.2003.09.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  BartelmezG. W.HoerrN. L. (1933). The vestibular club endings in ameiurus. Further evidence on the morphology of the synapse. J. Comp. Neurol.57, 401–428. 10.1002/cne.900570303

  • CrossRef
  • Google Scholar

• 9

  BillupsB.ForsytheI. D. (2002). Presynaptic mitochondrial calcium sequestration influences transmission at mammalian central synapses. J. Neurosci.22, 5840–5847.

  • Pubmed Abstract
  • Google Scholar

• 10

  CárdenasC.MillerR. A.SmithI.BuiT.MolgoJ.MullerM.et al. (2010). Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca²⁺ transfer to mitochondria. Cell142, 270–283. 10.1016/j.cell.2010.06.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  CastonguayA.RobitailleR. (2001). Differential regulation of transmitter release by presynaptic and glial Ca²⁺ internal stores at the neuromuscular synapse. J. Neurosci.21, 1911–1922.

  • Pubmed Abstract
  • Google Scholar

• 12

  CherraS. J.IIISteerE.GusdonA. M.KiselyovK.ChuC. T. (2013). Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am. J. Pathol.182, 474–484. 10.1016/j.ajpath.2012.10.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  ChicurelM. E.HarrisK. M. (1992). Three-dimensional analysis of the structure and composition of CA3 branched dendritic spines and their synaptic relationships with mossy fiber boutons in the rat hippocampus. J. Comp. Neurol.325, 169–182. 10.1002/cne.903250204

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  ChouhanA. K.IvannikovM. V.LuZ.SugimoriM.LlinasR. R.MacleodG. T. (2012). Cytosolic calcium coordinates mitochondrial energy metabolism with presynaptic activity. J. Neurosci.32, 1233–1243. 10.1523/jneurosci.1301-11.2012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  ClaphamD. E. (2007). Calcium signaling. Cell131, 1047–1058. 10.1016/j.cell.2007.11.028

  • CrossRef
  • Google Scholar

• 16

  CsordásG.GolenárT.SeifertE. L.KamerK. J.SancakY.PerocchiF.et al. (2013). MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca²⁺ uniporter. Cell Metab.17, 976–987. 10.1016/j.cmet.2013.04.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  CsordásG.VárnaiP.GolenárT.RoyS.PurkinsG.SchneiderT. G.et al. (2010). Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol. Cell39, 121–132. 10.1016/j.molcel.2010.06.029

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18

  DavidG.BarrettE. F. (2003). Mitochondrial Ca²⁺ uptake prevents desynchronization of quantal release and minimizes depletion during repetitive stimulation of mouse motor nerve terminals. J. Physiol.548, 425–438. 10.1113/jphysiol.2002.035196

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19

  De StefaniD.PatronM.RizzutoR. (2015). Structure and function of the mitochondrial calcium uniporter complex. Biochim. Biophys. Acta1853, 2006–2011. 10.1016/j.bbamcr.2015.04.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  DelucaH. F.EngstromG. W. (1961). Calcium uptake by rat kidney mitochondria. Proc. Natl. Acad. Sci. U S A47, 1744–1750. 10.1073/pnas.47.11.1744

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  EmptageN.BlissT. V.FineA. (1999). Single synaptic events evoke NMDA receptor-mediated release of calcium from internal stores in hippocampal dendritic spines. Neuron22, 115–124. 10.1016/s0896-6273(00)80683-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  EmptageN. J.ReidC. A.FineA. (2001). Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca²⁺ entry and spontaneous transmitter release. Neuron29, 197–208. 10.1016/s0896-6273(01)00190-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  FieniF.LeeS. B.JanY. N.KirichokY. (2012). Activity of the mitochondrial calcium uniporter varies greatly between tissues. Nat. Commun.3:1317. 10.1038/ncomms2325

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  FinchE. A.AugustineG. J. (1998). Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites. Nature396, 753–756. 10.1038/25541

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  FujimotoM.HayashiT. (2011). New insights into the role of mitochondria-associated endoplasmic reticulum membrane. Int. Rev. Cell Mol. Biol.292, 73–117. 10.1016/B978-0-12-386033-0.00002-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26

  FuruichiT.FurutamaD.HakamataY.NakaiJ.TakeshimaH.MikoshibaK. (1994). Multiple types of ryanodine receptor/Ca²⁺ release channels are differentially expressed in rabbit brain. J. Neurosci.14, 4794–4805.

  • Pubmed Abstract
  • Google Scholar

• 27

  FutatsugiA.KatoK.OguraH.LiS. T.NagataE.KuwajimaG.et al. (1999). Facilitation of NMDAR-independent LTP and spatial learning in mutant mice lacking ryanodine receptor type 3. Neuron24, 701–713. 10.1016/s0896-6273(00)81123-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28

  GalanteM.MartyA. (2003). Presynaptic ryanodine-sensitive calcium stores contribute to evoked neurotransmitter release at the basket cell-Purkinje cell synapse. J. Neurosci.23, 11229–11234.

  • Pubmed Abstract
  • Google Scholar

• 29

  Garcia-AlvarezG.LuB.YapK. A.WongL. C.ThevathasanJ. V.LimL.et al. (2015). STIM2 regulates PKA-dependent phosphorylation and trafficking of AMPARs. Mol. Biol. Cell26, 1141–1159. 10.1091/mbc.e14-07-1222

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  García-ChacónL. E.NguyenK. T.DavidG.BarrettE. F. (2006). Extrusion of Ca²⁺ from mouse motor terminal mitochondria via a Na⁺-Ca²⁺ exchanger increases post-tetanic evoked release. J. Physiol.574, 663–675. 10.1113/jphysiol.2006.110841

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  GazitN.VertkinI.ShapiraI.HelmM.SlomowitzE.SheibaM.et al. (2016). IGF-1 receptor differentially regulates spontaneous and evoked transmission via mitochondria at hippocampal synapses. Neuron89, 583–597. 10.1016/j.neuron.2015.12.034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  GianniniG.ContiA.MammarellaS.ScrobognaM.SorrentinoV. (1995). The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues. J. Cell Biol.128, 893–904. 10.1083/jcb.128.5.893

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  GrayE. G. (1963). Electron microscopy of presynaptic organelles of the spinal cord. J. Anat.97, 101–106.

  • Pubmed Abstract
  • Google Scholar

• 34

  GuoX.MacleodG. T.WellingtonA.HuF.PanchumarthiS.SchoenfieldM.et al. (2005). The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses. Neuron47, 379–393. 10.1016/j.neuron.2005.06.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  HartmannJ.KarlR. M.AlexanderR. P.AdelsbergerH.BrillM. S.RühlmannC.et al. (2014). STIM1 controls neuronal Ca²⁺ signaling, mGluR1-dependent synaptic transmission and cerebellar motor behavior. Neuron82, 635–644. 10.1016/j.neuron.2014.03.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36

  HendersonM. J.BaldwinH. A.WerleyC. A.BoccardoS.WhitakerL. R.YanX.et al. (2015). A low affinity GCaMP3 variant (GCaMPer) for imaging the endoplasmic reticulum calcium store. PLoS One10:e0139273. 10.1371/journal.pone.0139273

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37

  ItohS.ItoK.FujiiS.KanekoK.KatoK.MikoshibaK.et al. (2001). Neuronal plasticity in hippocampal mossy fiber-CA3 synapses of mice lacking the inositol-1,4,5-trisphosphate type 1 receptor. Brain Res.901, 237–246. 10.1016/s0006-8993(01)02373-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  JahnR.FasshauerD. (2012). Molecular machines governing exocytosis of synaptic vesicles. Nature490, 201–207. 10.1038/nature11320

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39

  KangJ. S.TianJ. H.PanP. Y.ZaldP.LiC.DengC.et al. (2008). Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell132, 137–148. 10.1016/j.cell.2007.11.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  KannO.KovácsR. (2007). Mitochondria and neuronal activity. Am. J. Physiol. Cell Physiol.292, C641–C657. 10.1152/ajpcell.00222.2006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  KapurA.YeckelM.JohnstonD. (2001). Hippocampal mossy fiber activity evokes Ca²⁺ release in CA3 pyramidal neurons via a metabotropic glutamate receptor pathway. Neuroscience107, 59–69. 10.1016/s0306-4522(01)00293-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  KasthuriN.HayworthK. J.BergerD. R.SchalekR. L.ConchelloJ. A.Knowles-BarleyS.et al. (2015). Saturated reconstruction of a volume of neocortex. Cell162, 648–661. 10.1016/j.cell.2015.06.054

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  KnopfelT. (2012). Genetically encoded optical indicators for the analysis of neuronal circuits. Nat. Rev. Neurosci.13, 687–700. 10.1523/JNEUROSCI.0381-14.2014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  KorkotianE.FrotscherM.SegalM. (2014). Synaptopodin regulates spine plasticity: mediation by calcium stores. J. Neurosci.34, 11641–11651. 10.1523/JNEUROSCI.0381-14.2014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  KornmannB. (2013). The molecular hug between the ER and the mitochondria. Curr. Opin. Cell Biol.25, 443–448. 10.1016/j.ceb.2013.02.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46

  KovalchukY.EilersJ.LismanJ.KonnerthA. (2000). NMDA receptor-mediated subthreshold Ca²⁺ signals in spines of hippocampal neurons. J. Neurosci.20, 1791–1799.

  • Pubmed Abstract
  • Google Scholar

• 47

  KwonS.SandoR.IIILewisT. L.HirabayashiY.MaximovA.PolleuxF. (2016). LKB1 regulates mitochondria-dependent presynaptic calcium clearance and neurotransmitter release properties at excitatory synapses along cortical axons. PLoS Biol.14:e1002516. 10.1371/journal.pbio.1002516

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  LauriS. E.BortolottoZ. A.NisticoR.BleakmanD.OrnsteinP. L.LodgeD.et al. (2003). A role for Ca²⁺ stores in kainate receptor-dependent synaptic facilitation and LTP at mossy fiber synapses in the hippocampus. Neuron39, 327–341. 10.1016/s0896-6273(03)00369-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49

  LeeD.LeeK. H.HoW. K.LeeS. H. (2007). Target cell-specific involvement of presynaptic mitochondria in post-tetanic potentiation at hippocampal mossy fiber synapses. J. Neurosci.27, 13603–13613. 10.1523/JNEUROSCI.3985-07.2007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  LeiS.PelkeyK. A.TopolnikL.CongarP.LacailleJ. C.McBainC. J. (2003). Depolarization-induced long-term depression at hippocampal mossy fiber-CA3 pyramidal neuron synapses. J. Neurosci.23, 9786–9795.

  • Pubmed Abstract
  • Google Scholar

• 51

  LiZ.OkamotoK.HayashiY.ShengM. (2004). The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell119, 873–887. 10.1016/j.cell.2004.11.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  LiangY.YuanL. L.JohnstonD.GrayR. (2002). Calcium signaling at single mossy fiber presynaptic terminals in the rat hippocampus. J. Neurophysiol.87, 1132–1137.

  • Pubmed Abstract
  • Google Scholar

• 53

  LlanoI.GonzalezJ.CaputoC.LaiF. A.BlayneyL. M.TanY. P.et al. (2000). Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients. Nat. Neurosci.3, 1256–1265. 10.1038/81781

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  LüscherC.MalenkaR. C. (2012). NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb Perspect. Biol.4:a005710. 10.1101/cshperspect.a005710

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  LyC. V.VerstrekenP. (2006). Mitochondria at the synapse. Neuroscientist12, 291–299. 10.1177/1073858406287661

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  MalenkaR. C.NicollR. A. (1999). Long-term potentiation–a decade of progress?Science285, 1870–1874. 10.1126/science.285.5435.1870

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  MallilankaramanK.DoonanP.CárdenasC.ChandramoorthyH. C.MüllerM.MillerR.et al. (2012). MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca²⁺ uptake that regulates cell survival. Cell151, 630–644. 10.1016/j.cell.2012.10.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  MarlandJ. R.HaselP.BonnycastleK.CousinM. A. (2016). Mitochondrial calcium uptake modulates synaptic vesicle endocytosis in central nerve terminals. J. Biol. Chem.291, 2080–2086. 10.1074/jbc.M115.686956

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  MathewS. S.HablitzJ. J. (2008). Calcium release via activation of presynaptic IP3 receptors contributes to kainate-induced IPSC facilitation in rat neocortex. Neuropharmacology55, 106–116. 10.1016/j.neuropharm.2008.05.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  MattsonM. P.GleichmannM.ChengA. (2008). Mitochondria in neuroplasticity and neurological disorders. Neuron60, 748–766. 10.1016/j.neuron.2008.10.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  MellorJ.NicollR. A. (2001). Hippocampal mossy fiber LTP is independent of postsynaptic calcium. Nat. Neurosci.4, 125–126. 10.1038/83941

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  MintaA.KaoJ. P.TsienR. Y. (1989). Fluorescent indicators for cytosolic calcium based on rhodamine and fluorescein chromophores. J. Biol. Chem.264, 8171–8178.

  • Pubmed Abstract
  • Google Scholar

• 63

  MironovS. L.SymonchukN. (2006). ER vesicles and mitochondria move and communicate at synapses. J. Cell Sci.119, 4926–4934. 10.1242/jcs.03254

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  MiyataM.FinchE. A.KhirougL.HashimotoK.HayasakaS.OdaS. I.et al. (2000). Local calcium release in dendritic spines required for long-term synaptic depression. Neuron28, 233–244. 10.1016/s0896-6273(00)00099-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  NagaiT.SawanoA.ParkE. S.MiyawakiA. (2001). Circularly permuted green fluorescent proteins engineered to sense Ca²⁺. Proc. Natl. Acad. Sci. U S A98, 3197–3202. 10.1073/pnas.051636098

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  NagaseT.ItoK. I.KatoK.KanekoK.KohdaK.MatsumotoM.et al. (2003). Long-term potentiation and long-term depression in hippocampal CA1 neurons of mice lacking the IP(3) type 1 receptor. Neuroscience117, 821–830. 10.1016/s0306-4522(02)00803-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  NeherE.SakabaT. (2008). Multiple roles of calcium ions in the regulation of neurotransmitter release. Neuron59, 861–872. 10.1016/j.neuron.2008.08.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  NishiyamaM.HongK.MikoshibaK.PooM. M.KatoK. (2000). Calcium stores regulate the polarity and input specificity of synaptic modification. Nature408, 584–588. 10.1038/35046067

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  OkuboY.SuzukiJ.KanemaruK.NakamuraN.ShibataT.IinoM. (2015). Visualization of Ca²⁺ filling mechanisms upon synaptic inputs in the endoplasmic reticulum of cerebellar purkinje cells. J. Neurosci.35, 15837–15846. 10.1523/JNEUROSCI.3487-15.2015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  OlietS. H.MalenkaR. C.NicollR. A. (1997). Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells. Neuron18, 969–982. 10.1016/s0896-6273(00)80336-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  PalayS. L. (1956). Synapses in the central nervous system. J. Biophys. Biochem. Cytol.2, 193–202. 10.1083/jcb.2.4.193

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  PalmerA. E.JinC.ReedJ. C.TsienR. Y. (2004). Bcl-2-mediated alterations in endoplasmic reticulum Ca²⁺ analyzed with an improved genetically encoded fluorescent sensor. Proc. Natl. Acad. Sci. U S A101, 17404–17409. 10.1073/pnas.0408030101

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  PalmerA. E.TsienR. Y. (2006). Measuring calcium signaling using genetically targetable fluorescent indicators. Nat. Protoc.1, 1057–1065. 10.1038/nprot.2006.172

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  PatronM.ChecchettoV.RaffaelloA.TeardoE.Vecellio ReaneD.MantoanM.et al. (2014). MICU1 and MICU2 finely tune the mitochondrial Ca²⁺ uniporter by exerting opposite effects on MCU activity. Mol. Cell53, 726–737. 10.1016/j.molcel.2014.01.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  PerocchiF.GohilV. M.GirgisH. S.BaoX. R.McCombsJ. E.PalmerA. E.et al. (2010). MICU1 encodes a mitochondrial EF hand protein required for Ca²⁺ uptake. Nature467, 291–296. 10.1038/nature09358

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  PlovanichM.BogoradR. L.SancakY.KamerK. J.StrittmatterL.LiA. A.et al. (2013). MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS One8:e55785. 10.1371/journal.pone.0055785

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  PoburkoD.Santo-DomingoJ.DemaurexN. (2011). Dynamic regulation of the mitochondrial proton gradient during cytosolic calcium elevations. J. Biol. Chem.286, 11672–11684. 10.1074/jbc.M110.159962

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  RaffaelloA.De StefaniD.SabbadinD.TeardoE.MerliG.PicardA.et al. (2013). The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J.32, 2362–2376. 10.1038/emboj.2013.157

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  RaymondC. R.RedmanS. J. (2002). Different calcium sources are narrowly tuned to the induction of different forms of LTP. J. Neurophysiol.88, 249–255.

  • Pubmed Abstract
  • Google Scholar

• 80

  ReyesM.StantonP. K. (1996). Induction of hippocampal long-term depression requires release of Ca²⁺ from separate presynaptic and postsynaptic intracellular stores. J. Neurosci.16, 5951–5960.

  • Pubmed Abstract
  • Google Scholar

• 81

  RizzutoR.BriniM.MurgiaM.PozzanT. (1993). Microdomains with high Ca²⁺ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science262, 744–747. 10.1126/science.8235595

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  RizzutoR.De StefaniD.RaffaelloA.MammucariC. (2012). Mitochondria as sensors and regulators of calcium signalling. Nat. Rev. Mol. Cell Biol.13, 566–578. 10.1038/nrm3412

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  RizzutoR.PozzanT. (2006). Microdomains of intracellular Ca²⁺: molecular determinants and functional consequences. Physiol. Rev.86, 369–408. 10.1152/physrev.00004.2005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  RizzutoR.SimpsonA. W.BriniM.PozzanT. (1992). Rapid changes of mitochondrial Ca²⁺ revealed by specifically targeted recombinant aequorin. Nature358, 325–327. 10.1038/358325a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  RobertV.GurliniP.ToselloV.NagaiT.MiyawakiA.Di LisaF.et al. (2001). Beat-to-beat oscillations of mitochondrial [Ca²⁺] in cardiac cells. EMBO J.20, 4998–5007. 10.1093/emboj/20.17.4998

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  Rodriguez-GarciaA.Rojo-RuizJ.Navas-NavarroP.AulestiaF. J.Gallego-SandinS.Garcia-SanchoJ.et al. (2014). GAP, an aequorin-based fluorescent indicator for imaging Ca²⁺ in organelles. Proc. Natl. Acad. Sci. U S A111, 2584–2589. 10.1073/pnas.1316539111

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  RoseT.GoltsteinP. M.PortuguesR.GriesbeckO. (2014). Putting a finishing touch on GECIs. Front. Mol. Neurosci.7:88. 10.3389/fnmol.2014.00088

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  RowlandK. C.IrbyN. K.SpirouG. A. (2000). Specialized synapse-associated structures within the calyx of Held. J. Neurosci.20, 9135–9144.

  • Pubmed Abstract
  • Google Scholar

• 89

  SancakY.MarkhardA. L.KitamiT.Kovács-BogdánE.KamerK. J.UdeshiN. D.et al. (2013). EMRE is an essential component of the mitochondrial calcium uniporter complex. Science342, 1379–1382. 10.1126/science.1242993

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  SandlerV. M.BarbaraJ. G. (1999). Calcium-induced calcium release contributes to action potential-evoked calcium transients in hippocampal CA1 pyramidal neurons. J. Neurosci.19, 4325–4336.

  • Pubmed Abstract
  • Google Scholar

• 91

  SchneggenburgerR.NeherE. (2005). Presynaptic calcium and control of vesicle fusion. Curr. Opin. Neurobiol.15, 266–274. 10.1016/j.conb.2005.05.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  SchonE. A.PrzedborskiS. (2011). Mitochondria: the next (neurode)generation. Neuron70, 1033–1053. 10.1016/j.neuron.2011.06.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  ScullinC. S.PartridgeL. D. (2010). Contributions of SERCA pump and ryanodine-sensitive stores to presynaptic residual Ca²⁺. Cell Calcium47, 326–338. 10.1016/j.ceca.2010.01.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  ScullinC. S.WilsonM. C.PartridgeL. D. (2010). Developmental changes in presynaptic Ca²⁺ clearance kinetics and synaptic plasticity in mouse Schaffer collateral terminals. Eur. J. Neurosci.31, 817–826. 10.1111/j.1460-9568.2010.07137.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  SegalM.KorkotianE. (2015). Roles of calcium stores and store-operated channels in plasticity of dendritic spines. Neuroscientist [Epub ahead of print]. 10.1177/1073858415613277

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  SharmaG.VijayaraghavanS. (2003). Modulation of presynaptic store calcium induces release of glutamate and postsynaptic firing. Neuron38, 929–939. 10.1016/s0896-6273(03)00322-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  SharpA. H.McPhersonP. S.DawsonT. M.AokiC.CampbellK. P.SnyderS. H. (1993). Differential immunohistochemical localization of inositol 1,4,5-trisphosphate- and ryanodine-sensitive Ca²⁺ release channels in rat brain. J. Neurosci.13, 3051–3063.

  • Pubmed Abstract
  • Google Scholar

• 98

  SharpA. H.NuciforaF. C.Jr.BlondelO.SheppardC. A.ZhangC.SnyderS. H.et al. (1999). Differential cellular expression of isoforms of inositol 1,4,5-triphosphate receptors in neurons and glia in brain. J. Comp. Neurol.406, 207–220. 10.1002/(SICI)1096-9861(19990405)406:2<207::AID-CNE6>3.0.CO;2-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  ShengM.HoogenraadC. C. (2007). The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu. Rev. Biochem.76, 823–847. 10.1146/annurev.biochem.76.060805.160029

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  ShepherdG. M.HarrisK. M. (1998). Three-dimensional structure and composition of CA3→CA1 axons in rat hippocampal slices: implications for presynaptic connectivity and compartmentalization. J. Neurosci.18, 8300–8310.

  • Pubmed Abstract
  • Google Scholar

• 101

  Shoshan-BarmatzV.ZalkR.GincelD.VardiN. (2004). Subcellular localization of VDAC in mitochondria and ER in the cerebellum. Biochim. Biophys. Acta1657, 105–114. 10.1016/j.bbabio.2004.02.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  SlaterE. C.ClelandK. W. (1953). The effect of calcium on the respiratory and phosphorylative activities of heart-muscle sarcosomes. Biochem. J.55, 566–590. 10.1042/bj0550566

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  SolovyovaN.VeselovskyN.ToescuE. C.VerkhratskyA. (2002). Ca²⁺ dynamics in the lumen of the endoplasmic reticulum in sensory neurons: direct visualization of Ca²⁺-induced Ca²⁺ release triggered by physiological Ca²⁺ entry. EMBO J.21, 622–630. 10.1093/emboj/21.4.622

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  SpacekJ.HarrisK. M. (1997). Three-dimensional organization of smooth endoplasmic reticulum in hippocampal CA1 dendrites and dendritic spines of the immature and mature rat. J. Neurosci.17, 190–203. 10.1002/hipo.20238

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  SüdhofT. C. (2012). The presynaptic active zone. Neuron75, 11–25. 10.1016/j.neuron.2012.06.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  SuzukiJ.KanemaruK.IshiiK.OhkuraM.OkuboY.IinoM. (2014). Imaging intraorganellar Ca²⁺ at subcellular resolution using CEPIA. Nat. Commun.5:4153. 10.1038/ncomms5153

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  TakechiH.EilersJ.KonnerthA. (1998). A new class of synaptic response involving calcium release in dendritic spines. Nature396, 757–760. 10.1038/25547

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  TakeiK.StukenbrokH.MetcalfA.MigneryG. A.SüdhofT. C.VolpeP.et al. (1992). Ca²⁺ stores in Purkinje neurons: endoplasmic reticulum subcompartments demonstrated by the heterogeneous distribution of the InsP3 receptor, Ca²⁺-ATPase and calsequestrin. J. Neurosci.12, 489–505.

  • Pubmed Abstract
  • Google Scholar

• 109

  TangY.ZuckerR. S. (1997). Mitochondrial involvement in post-tetanic potentiation of synaptic transmission. Neuron18, 483–491. 10.1016/s0896-6273(00)81248-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  ThayerS. A.MillerR. J. (1990). Regulation of the intracellular free calcium concentration in single rat dorsal root ganglion neurones in vitro. J. Physiol.425, 85–115. 10.1113/jphysiol.1990.sp018094

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  TianL.HiresS. A.LoogerL. L. (2012). Imaging neuronal activity with genetically encoded calcium indicators. Cold Spring Harb. Protoc.2012, 647–656. 10.1101/pdb.top069609

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  UnniV. K.ZakharenkoS. S.ZablowL.DeCostanzoA. J.SiegelbaumS. A. (2004). Calcium release from presynaptic ryanodine-sensitive stores is required for long-term depression at hippocampal CA3-CA3 pyramidal neuron synapses. J. Neurosci.24, 9612–9622. 10.1523/JNEUROSCI.5583-03.2004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  VerkhratskyA. (2005). Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol. Rev.85, 201–279. 10.1152/physrev.00004.2004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  VerstrekenP.LyC. V.VenkenK. J.KohT. W.ZhouY.BellenH. J. (2005). Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron47, 365–378. 10.1016/j.neuron.2005.06.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  VoelkerD. R. (1990). Characterization of phosphatidylserine synthesis and translocation in permeabilized animal cells. J. Biol. Chem.265, 14340–14346.

  • Pubmed Abstract
  • Google Scholar

• 116

  VosM.LauwersE.VerstrekenP. (2010). Synaptic mitochondria in synaptic transmission and organization of vesicle pools in health and disease. Front. Synaptic Neurosci.2:139. 10.3389/fnsyn.2010.00139

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  WangS. S.DenkW.HäusserM. (2000). Coincidence detection in single dendritic spines mediated by calcium release. Nat. Neurosci.3, 1266–1273. 10.1038/81792

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  WangX.SchwarzT. L. (2009). The mechanism of Ca²⁺ -dependent regulation of kinesin-mediated mitochondrial motility. Cell136, 163–174. 10.1016/j.cell.2008.11.046

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  WangG. J.ThayerS. A. (2002). NMDA-induced calcium loads recycle across the mitochondrial inner membrane of hippocampal neurons in culture. J. Neurophysiol.87, 740–749.

  • Pubmed Abstract
  • Google Scholar

• 120

  WhiteR. J.ReynoldsI. J. (1995). Mitochondria and Na⁺/Ca²⁺ exchange buffer glutamate-induced calcium loads in cultured cortical neurons. J. Neurosci.15, 1318–1328.

  • Pubmed Abstract
  • Google Scholar

• 121

  WuJ.ProleD. L.ShenY.LinZ.GnanasekaranA.LiuY.et al. (2014). Red fluorescent genetically encoded Ca²⁺ indicators for use in mitochondria and endoplasmic reticulum. Biochem. J.464, 13–22. 10.1042/bj20140931

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  YangS. N.TangY. G.ZuckerR. S. (1999). Selective induction of LTP and LTD by postsynaptic [Ca²⁺]_i elevation. J. Neurophysiol.81, 781–787.

  • Pubmed Abstract
  • Google Scholar

• 123

  YeckelM. F.KapurA.JohnstonD. (1999). Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism. Nat. Neurosci.2, 625–633. 10.1038/10180

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  YoungK. W.BamptonE. T.PinònL.BanoD.NicoteraP. (2008). Mitochondrial Ca²⁺ signalling in hippocampal neurons. Cell Calcium43, 296–306. 10.1016/j.ceca.2007.06.007

  • CrossRef
  • Google Scholar

• 125

  ZhongN.BeaumontV.ZuckerR. S. (2001). Roles for mitochondrial and reverse mode Na⁺/Ca²⁺ exchange and the plasmalemma Ca²⁺ ATPase in post-tetanic potentiation at crayfish neuromuscular junctions. J. Neurosci.21, 9598–9607.

  • Pubmed Abstract
  • Google Scholar

• 126

  ZhangH.SunS.HerremanA.De StrooperB.BezprozvannyI. (2010). Role of presenilins in neuronal calcium homeostasis. J. Neurosci.30, 8566–8580. 10.1523/JNEUROSCI.1554-10.2010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  ZuckerR. S. (1989). Short-term synaptic plasticity. Annu. Rev. Neurosci.12, 13–31. 10.1146/annurev.neuro.12.1.13

  • Pubmed Abstract
  • CrossRef
  • Google Scholar