Abstract
Growth factors play important roles in synapse formation. Mouse models of neuropsychiatric diseases suggest that defects in synaptogenic growth factors, their receptors, and signaling pathways can lead to disordered neural development and various behavioral phenotypes, including anxiety, memory problems, and social deficits. Genetic association studies in humans have found evidence for similar relationships between growth factor signaling pathways and neuropsychiatric phenotypes. Accumulating data suggest that dysfunction in neuronal circuitry, caused by defects in growth factor-mediated synapse formation, contributes to the susceptibility to multiple neuropsychiatric diseases, including epilepsy, autism, and disorders of thought and mood (e.g., schizophrenia and bipolar disorder, respectively). In this review, we will focus on how specific synaptogenic growth factors and their downstream signaling pathways might be involved in the development of neuropsychiatric diseases.
Introduction
Neuropsychiatric diseases are increasingly recognized to have developmental origins. Some of these illnesses, such as autism and ADHD, must be diagnosed based on symptoms identified during early childhood (Association, 2013). Others, such as bipolar disorder and schizophrenia, are usually diagnosed in adulthood, but are recognized to have some manifestations in childhood as well (Martin and Smith, 2013; Schulz et al., 2014). Although these illnesses were initially studied in isolation from each other, there is increasing evidence that these clinically disparate diseases may have common genetic origins (Smoller and Finn, 2003; Lichtenstein et al., 2010; Sullivan et al., 2012; Cross-Disorder Group of the Psychiatric Genomics et al., 2013). To take this idea further, if these diseases begin early in development and have identifiable common genetic origins, it is possible, and perhaps even likely, that perturbations in some common developmental pathways may be involved in their pathogenesis.
One major set of signaling molecules that are important in neural development are synaptogenic growth factors. These growth factors, including brain-derived neurotrophic factor (BDNF), the fibroblast growth factor (FGF) family, Wnts, and insulin-like growth factors (IGFs), are important not only in cell fate specification and neurogenesis, but specifically in the formation and maintenance of synapses (Vicario-Abejon et al., 1998; Barros et al., 2009; Terauchi et al., 2010; Guillemot and Zimmer, 2011; Corvin et al., 2012; Rosso and Inestrosa, 2013). Appropriate partnering of pre- and postsynaptic neurons is critical for the establishment of individual neuronal circuits, which in turn is the fundamental basis of overall wiring of the functional brain. Problems in these synaptogenic signaling pathways, which could occur either due to mutations in individual growth factors or their receptors, or inappropriate conduction of those signals through intracellular signaling pathways, could lead to abnormal connections between neurons or aberrant neuronal circuitry (Figure 1).
Figure 1
Several lines of evidence suggest that synaptogenic growth factors are involved in the pathogenesis of neuropsychiatric diseases. First, it is known that many mouse models with mutations in synaptogenic growth factors or their receptors have behavioral abnormalities, which may be analogous to neuropsychiatric disease in humans. For example, mice lacking FGF7 are predisposed to epilepsy in a kindling protocol (Terauchi et al., 2010). Second, some humans with mutations in growth factors have observable behavioral and cognitive problems. For example, people with a valine to methionine substitution at position 66 (V66M) in the proBDNF polypeptide have impaired episodic memory and increased risk of mood disorders (Egan et al., 2003; Schumacher et al., 2005). Finally, there is growing evidence that maintenance of proper networks and synaptogenesis and plasticity are impaired in neuropsychiatric illnesses (Brennand et al., 2011; Uddin et al., 2013), and growth factors are known to have a major role in all of these processes.
We propose that the critical stage of interest for studying these illnesses is during synaptogenesis, as this is when neurons are wired together to form functional circuits. For our purposes, “synaptogenesis” includes synapse development, maturation, and maintenance, as these steps are all essential for a mature, functional synapse. It is important to note that synapse maturation and modulation occur throughout life, and are likely to contribute to variations in disease presentation as development progresses. For example, FGF2 has been hypothesized as an “on-line” modulator of mood and anxiety in adults (Turner et al., 2006). Synaptogenic growth factors are released from both the pre- and postsynaptic neurons to assist synaptogenesis (Figure 2). Other developmental processes, such as neurogenesis and programmed cell death are also important in brain development, and occur throughout life; their potential contributions to the pathogenesis of neuropsychiatric diseases have been reviewed elsewhere (Margolis et al., 1994; Mennerick and Zorumski, 2000; Gigante et al., 2011; Petrik et al., 2012).
Figure 2
There are many molecules that act as synaptogenic growth factors in the brain. The most well-studied of these is BDNF, which has been linked to multiple neuropsychiatric diseases including bipolar disorder, depression, and schizophrenia (Neves-Pereira et al., 2002, 2005; Schumacher et al., 2005). The FGFs are a large family of growth factors, which are important in many processes throughout development. FGFs have recently been shown to be important in the development of glutamatergic and GABAergic synapses (Flajolet et al., 2008; Stevens et al., 2010; Terauchi et al., 2010) and have been implicated in a wide number of neuropsychiatric diseases (Evans et al., 2004; Perez et al., 2009; Terwisscha Van Scheltinga et al., 2010; Yamanaka et al., 2011; Turner et al., 2012). Wnts and their receptors have been implicated in learning and memory (Tabatadze et al., 2012; Fortress et al., 2013), autism (Wassink et al., 2001), and some forms of epilepsy (Lako et al., 1998). Although the insulin-like growth factor (IGF) family of factors and receptors was previously recognized primarily for its importance in neurogenesis, development, and aging, this family is also now known to have roles in cortical plasticity (Tropea et al., 2006) and memory (Chen et al., 2011). Other families of growth factors have also been shown to be active in synaptogenesis and brain development, such as the TGFβ, GDNF, and EGF/neuregulin families (Mei and Xiong, 2008; Paratcha and Ledda, 2008; Williamson and Hiesinger, 2008; Van Kesteren et al., 2008; Krieglstein et al., 2011). The contributions of growth factors are summarized in Table 1.
Table 1
Growth factors and their receptors in synaptogenesis and neuropsychiatric disease.
Growth factors proposed to be involved in brain development are listed, along with available evidence for their involvement in neuropsychiatric disease. Evidence from animal models is listed in blue, evidence from studies in humans or tissue derived from humans is listed in orange. Abbreviations used: 3 '-UTR, 3 '-untranslated region; AD, Alzheimer disease; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF, brain-derived neurotrophic factor; CA3, cornu ammonis area 3; CATSHL, camptodactyly, tall stature, scoliosis, and hearing loss; CNS, central nervous system; DG, dentate gyrus; EGF, epidermal growth factor; ES cell, embryonic stem cell; Fz, Frizzled receptor; GDNF, glial-derived neurotrophic factor; GH, growth hormone; GluR, AMPA glutamate receptor subunit; JNK, c-Jun N-terminal kinase; LTP, long-term potentiation; MDD, major depressive disorder; miR, microRNA; MMSE, mini-mental status exam; NGF, nerve growth factor; NRG, neuregulin; NT-3, neurotrophin-3; NT-4, neurotrophin-4; OCD, obsessive compulsive disorder; PD, Parkinson disease; PFC, prefrontal cortex; PTZ, pentylenetetrazol; RNAi, RNA interference; Ryk, atypical receptor tyrosine kinase; SADDAN, severe achondroplasia with developmental delay and acanthosis nigricans; SNP, single nucleotide polymorphism; TGF, transforming growth factor; vmPFC, ventromedial prefrontal cortex; WAGRO, wilms tumor, aniridia, genitourinary anomalies, mental retardation, and obesity syndrome.
Growth factor signaling between pre- and postsynaptic neurons ensures that proper connections between both individual neurons and brain regions are made. Here we describe how dysregulation of these systems may lead to neuropsychiatric disease. Since many of these synaptogenic growth factors promote intracellular signaling through common signal transduction pathways, it is possible that modulation of one or a few of these pathways could lead to significant improvement of clinical symptoms.
BDNF and the neurotrophin family of growth factors
The neurotrophin family of growth factors includes BDNF, pro-BDNF, NGF, NT-3, and NT-4. Neurotrophins bind to the Trk family of receptors, as well as the p75 receptor, to activate multiple intracellular signaling cascades. BDNF binds primarily to TrkB, NGF to TrkA, NT-3 to TrkC and TrkB, and NT-4 primarily to TrkB. All neurotrophins bind with relatively low affinity to the p75 receptor, and proBDNF binds only the p75 receptor. When neurotrophins bind to Trks, they support the survival and growth of neurons. Neurotrophins secreted from the postsynaptic cell promote the survival and health of the presynaptic neuron, and maintain a synapse between the two cells. One exception to this rule is the binding of proBDNF to p75, which is usually a pro-apoptotic signal to neurons (Teng et al., 2005). BDNF may also participate in postsynaptic organization (Johnson-Venkatesh and Umemori, 2010; Yoshii et al., 2011), but it is unclear whether this is independent of its presynaptic organizational activities.
BDNF signaling plays a major role in CNS synaptogenesis. It is involved in development of both excitatory and inhibitory synapses (Itami et al., 2000; Fiorentino et al., 2009), and is important for strengthening excitatory synapses through long-term potentiation, a form of cellular and network learning and memory (Minichiello, 2009). BDNF is released from neurons both constitutively and in an activity-dependent fashion (Farhadi et al., 2000; Zha et al., 2001; Egan et al., 2003), and its activity-dependent expression is important for the development and maintenance of cortical inhibitory synapses (Hong et al., 2008). Mice with a hypomorphic or null TrkB allele in hindbrain neurons demonstrate impaired climbing fiber pruning at the climbing fiber-Purkinje cell synapse (Johnson et al., 2007), suggesting that TrkB signaling is important for developmental synaptic pruning, possibly in an activity-dependent fashion. BDNF also plays a role in shaping dendritic morphology, which is an important aspect of synaptogenesis. Mice homozygous (knock-in) for the V66M BDNF mutation show decreased cortical spine density and diameter (Liu et al., 2012), as well as decreased hippocampal and cortical dendritic complexity (Chen et al., 2006b; Yu et al., 2009). BDNF is upregulated in mouse hippocampus under conditions of environmental enrichment (Hu et al., 2013), which is known to enhance dendritic arborization (Turner et al., 2003) and number of hippocampal synapses (Gogolla et al., 2009; Babic and Zinsmaier, 2011). BDNF may have differential effects depending on where its mRNA is translated in the cell; recent evidence shows that somatic BDNF is important for dendritic spine formation, whereas dendritic BDNF expression is important for spine head growth and spine pruning (Orefice et al., 2013). Other neurotrophins, including NT-3 and NT-4, have not been shown conclusively to be involved in synaptogenesis; these do have importance in neurogenesis and other aspects of CNS development (Table 1).
BDNF has been implicated in the pathogenesis of multiple neuropsychiatric diseases, including depression (Schumacher et al., 2005), schizophrenia (Zintzaras, 2007), and Rett syndrome, a severe developmental disorder with autistic features (Larimore et al., 2009; Zeev et al., 2009). The V66M mutation in BDNF impairs activity-dependent release of BDNF in hippocampal cultures and is associated with impaired episodic memory, both in patients with schizophrenia and people without neurologic or psychiatric illness (Egan et al., 2003). Interestingly, this mutation may be both a risk factor for depression (Schumacher et al., 2005) and a protective factor against bipolar disorder (Geller et al., 2004), although not all genetic studies in humans support these associations (Neves-Pereira et al., 2002). Data from post-mortem patient tissue supports changes in mRNA and protein levels of BDNF and TrkB in patients with mood and psychotic disorders (Issa et al., 2010; Thompson Ray et al., 2011; Tripp et al., 2012; Qi et al., 2013). Data from animal models with deficits in neurotrophin signaling support the links between BDNF signaling and behavior. Mice lacking TrkB in forebrain neurons show impaired spatial learning, delay in fear conditioning, and impaired hippocampal LTP (Minichiello et al., 1999), as well as behavioral rigidity when faced with changing environmental conditions (Vyssotski et al., 2002). Another group, using the same forebrain-specific TrkB knockout mice, observed increased behavioral hyperactivity and impulsivity (Zorner et al., 2003). Mice with reduced BDNF expression levels display increased alcohol consumption (Hensler et al., 2003; McGough et al., 2004). The same is observed in mice when trkB expression levels are reduced (Jeanblanc et al., 2006). Although it is unknown whether NT-4 functions specifically in synaptogenesis, NT-4 null mice have deficits in fear conditioning and hippocampal LTP (Xie et al., 2000), which may have implications for human anxiety and cognitive disorders.
Fibroblast growth factors and their receptors
The FGF family includes 22 FGF genes, which are clustered into groups based on phylogenetic similarity and receptor specificity (Umemori, 2009). Among them, there are 4 FGF homologous factors (originally called FGFs 11–14, now known as FHFs), which are solely intracellular signaling molecules and do not bind to FGF receptors (FGFRs). Other FGFs bind to FGFRs, of which there are 4 genes that can be alternatively spliced into multiple receptor subtypes (Umemori, 2009). FGF signaling is important in organogenesis and growth throughout development (Beenken and Mohammadi, 2009). In the CNS, FGFs have many functions, including neurogenesis, fate specification, and neuronal survival (Dono, 2003; Mason, 2007). FGFs also play roles in axon guidance and target recognition. For example, FGF8 has been shown to be an axon guidance molecule for trochlear nerve axons in a cultured rat midbrain explant model of neuronal pathfinding (Irving et al., 2002), and FGF2 gradients help retinal ganglion cell axons find their targets in the optic tectum in developing Xenopus (McFarlane et al., 1995). Although some FGFs act by an endocrine mechanism in the periphery, (such as FGF19, FGF21, and FGF23), FGFs that are active in the CNS are released by postsynaptic cells to stimulate presynaptic organization (Terauchi et al., 2010), and therefore act primarily by local mechanisms within the CNS.
Evidence is accumulating for the importance of FGFs in synaptogenesis. In cultured rat hippocampal neurons, addition of FGF2 to the culture medium generates an increase in excitatory synapses via a MAPK-dependent mechanism (Li et al., 2002). In cultured neurons, FGF7 and FGF22 function as presynaptic organizers (Umemori et al., 2004; Terauchi et al., 2010). FGF7-null mice have a deficit in hippocampal inhibitory synapse formation while FGF22-null mice are deficient in hippocampal excitatory synapses (Terauchi et al., 2010), consistent with the roles of FGF7 and FGF22 in presynaptic organization (Umemori et al., 2004). Other FGFs, including FGFs 4, 6, and 9 also promote synaptic vesicle clustering in cultured neurons (Umemori et al., 2004), but their roles in synaptogenesis in vivo are unknown.
The evidence linking FGFs and behavioral abnormalities is growing. FGF7-null are prone to develop epilepsy after kindling, while FGF22-null are resistant to seizure induction (Terauchi et al., 2010), providing a link between synaptogenic defects and a neurobehavioral phenotype. Mice overexpressing FGF21 primarily in the liver, which is known to function in metabolism and insulin sensitivity, also show dysregulation in circadian rhythms, which is a common feature of mood disorders (Bookout et al., 2013); it is unknown whether these mice have other behavioral abnormalities consistent with mood alterations. It is also unknown whether FGF21 plays a role in synaptogenesis, although it is known to cross the blood-brain barrier (Bookout et al., 2013). Mice globally lacking FGF17 have impaired social interactions, a key diagnostic feature of autism (Scearce-Levie et al., 2008). Interestingly, FGF17 was found to induce neurite branching in cultured neurons (Umemori et al., 2004), suggestive that abnormal connectivity between neurons may underlie these behavioral changes in FGF17-null mice. Peripheral administration of FGF2 to rats with endogenously high levels of anxiety was found to reduce anxiety-like behaviors (Perez et al., 2009), while lentiviral shRNA-mediated knockdown of FGF2 in rat hippocampus increased anxiety-like behaviors (Eren-Kocak et al., 2011). Although no studies of FGF expression in anxiety disorder patients have been published, the body of literature supports the idea that FGF2, if not other FGFs, is an important regulator of many emotional states. Alterations in FGF expression in humans have also been associated with depression (Evans et al., 2004), substance abuse (Turner et al., 2012), and schizophrenia (Terwisscha Van Scheltinga et al., 2010). Mutations in FGFR2 are causative for Pfeiffer Syndrome, some severe forms of which manifest intellectual disability (Priolo et al., 2000; Shotelersuk et al., 2002). There are multiple other examples of FGFs and FGFRs linked to neuropsychiatric disease, which are detailed in Table 1. Overall, the data underscore the importance of normal FGF signaling both for normal synapse formation and normal neuropsychiatric functioning.
Wnt signaling molecules and their receptors
Wnts are a family of 19 highly-conserved secreted signaling glycoproteins that play important roles in embryogenesis and fate specification in early development. When they bind to their receptors, the Frizzled proteins and LRP coreceptors, they can trigger several different types of intracellular signaling pathways. The best characterized intracellular signaling pathway is the Wnt/Frizzled/β-catenin/GSK3-β pathway, also known as the canonical pathway. Wnts 1, 2, 3a, 7a, and 7b generally signal through the canonical pathway. There are also several non-canonical pathways that have been identified which do not signal via β-catenin, the most well-studied of which are the planar cell polarity (PCP) and the Wnt/calcium pathways. Wnts 4a and 5a signal through the PCP pathway, which is involved in neuronal migration as well as cell polarity (Okerlund and Cheyette, 2011). The Wnt/calcium pathway is important for control of calcium release from the endoplasmic reticulum (ER) for calcium-dependent intracellular signals (De, 2011). There are also a number of other Wnt signaling pathways, but these are generally less well-understood (Niehrs, 2012). Although Frizzled and LRP are the most well-studied receptors for Wnts, Wnts are also known to bind to many other cell surface receptors, including Ryk, ROR2, and others (Niehrs, 2012).
Wnt signaling pathways have many roles in CNS synaptogenesis, and can both increase or decrease synapse formation depending on the Wnt pathways and cell types involved. The role of Wnts in non-mammalian and peripheral nervous system synaptogenesis has been reviewed extensively elsewhere (Park and Shen, 2012; Poon et al., 2013). Wnt7a is a retrograde signal derived from cerebellar granule cells to presynaptic mossy fiber terminals in the cerebellum (Hall et al., 2000). Wnt7a binds to Dvl1, a mouse homolog of Disheveled, and induces clustering of synapsin I and axon growth cone remodeling (Hall et al., 2000; Ahmad-Annuar et al., 2006). In mice globally lacking either Wnt7a or Dvl1, there are deficits in cerebellar synapse formation, while mice null for both Wnt7a and Dvl1 have an additional defect in neurotransmitter release at mossy fiber-granule cell synapses (Hall et al., 2000; Ahmad-Annuar et al., 2006). Wnt7a also has a role in synaptic differentiation in the hippocampus, particularly enhancing the number and strength of excitatory synapses (Davis et al., 2008; Ciani et al., 2011); this is also true for Wnt7b (Davis et al., 2008). Wnt5a has been shown to increase the formation of glutamatergic synapses and maturation of dendritic spines in cultured neurons via a calcium-dependent mechanism (Varela-Nallar et al., 2010). However, in a separate study, application of Wnt5a to neuronal cultures resulted in a decrease in glutamatergic synapses (Davis et al., 2008), suggesting that Wnt5a effects may be dependent on culture conditions or downstream signaling pathways (canonical vs. non-canonical). Taken together, the data demonstrate the importance of Wnt signaling in synaptogenesis in both pre- and postsynaptic compartments.
Although many knockout mouse models for Wnts have been developed, most do not survive embryogenesis (Uusitalo et al., 1999; Van Amerongen and Berns, 2006), and therefore cannot be assessed for behavioral phenotypes. However, there are mouse models where other mediators of Wnt signaling have been genetically manipulated, which implicate Wnt signaling in behavior. Mice null for Dvl1 have diminished social interactions, a core feature of autism, as well as abnormal prepulse inhibition, which is observed in both autism and schizophrenia (Lijam et al., 1997). These mice also have deficits in hippocampal dendritic branching and cerebellar synaptogenesis (Lijam et al., 1997; Rosso et al., 2005). Forebrain-specific reduction of expression of β-catenin, the putative downstream signaling molecule for Dvl1, generates subtle behavioral changes in the tail suspension test, a depression-like endophenotype (Gould et al., 2008). The lack of similar behavioral deficits between the forebrain-specific β-catenin knockout and Dvl1-null mice could be due to the fact that the β-catenin knockout was limited to the forebrain, whereas the synaptic changes noted in Dvl1-null mice are primarily noted in hippocampus and cerebellum, or may be attributable to the multiplicity of downstream effectors of Wnt signaling. Another way to modulate Wnt signaling is by overexpressing Axin, a scaffolding protein that negatively regulates Wnt signaling. When mice overexpressing Axin are trained in a fear-conditioning paradigm, they exhibit an increase in freezing to contextual conditioning as well as changes in cued fear conditioning, suggestive that alterations in Wnt signaling could increase anxiety-related behaviors (Kim et al., 2011).
Wnts have been implicated in multiple genetic studies of human neuropsychiatric disease. Some data suggest that mutations in Wnt2 are linked with forms of autism with severe language deficits (Wassink et al., 2001), although not all studies have confirmed this association (McCoy et al., 2002). Interestingly, the CHD8 gene has been identified in multiple genetic studies of autism and related neurodevelopmental disorders (Neale et al., 2012; O'Roak et al., 2012a,b; Talkowski et al., 2012). The CHD8 protein binds β-catenin and negatively regulates Wnt/β-catenin signaling (Nishiyama et al., 2012). Wnts also can activate the retinoid-related orphan receptor alpha, RORA, which has been implicated by GWAS in several neuropsychiatric diseases, including autism (Nguyen et al., 2010; Sarachana and Hu, 2013), bipolar disorder (Le-Niculescu et al., 2009; but see McGrath et al., 2009), depression (Terracciano et al., 2010; Utge et al., 2010), and PTSD (Logue et al., 2013). Additionally, both lithium and valproic acid, medications commonly used to treat neuropsychiatric diseases, are known to inhibit GSK3β, a downstream effector of the canonical Wnt signaling pathway (Lucas and Salinas, 1997; Hall et al., 2002), and lithium treatment in mice activates Wnt signaling in various regions of the brain including amygdala and hippocampus (O'Brien et al., 2004).
Insulin-like growth factors and their receptors
IGFs are peptide growth factors identified based on their similarity to the peptide hormone, insulin. The family consists of two growth factor ligands (IGF1 and IGF2), two receptors (IGF1R and IGF2R), and multiple IGF binding proteins (IGFBPs) and IGFBP-related proteins (Fernandez and Torres-Aleman, 2012). IGF1 is a neurotrophic factor that enhances the survival of neurons in culture (Meyer-Franke et al., 1995; Arnaldez and Helman, 2012; O'Kusky and Ye, 2012). IGF2 has also been implicated in neurogenesis, synaptogenesis, myelination, and dendritic branching (Agis-Balboa et al., 2011; Fernandez and Torres-Aleman, 2012; Schmeisser et al., 2012). The mechanism of IGF1 action on neurons may be both endocrine and autocrine, as it circulates in the bloodstream and can cross the blood-brain barrier, in addition to being secreted locally by neurons (Nunez et al., 2003) (Figure 2). IGF2 may also serve a neurotrophic function, at least for young hippocampal neurons, since increasing IGF2/IGFBP7 signaling via a fear-conditioning paradigm in mice leads to enhanced survival of newborn hippocampal neurons (Agis-Balboa et al., 2011).
The primary physiologic receptor for the IGFs is IGF1R, although IGF1 can also bind the insulin receptor. Like many growth factor receptors, IGF1R is a receptor tyrosine kinase, and when bound by IGF1, can activate several different intracellular cascades (Arnaldez and Helman, 2012). IGF2R can bind IGF2, but not IGF1. IGF2R is thought primarily to sequester IGF2 at the cell surface, and in most cases this binding does not generate transmembrane signals. IGFBPs regulate IGF activity by binding to IGFs and IGF1R, and this binding can inhibit or facilitate the binding of IGFs to IGF1R, or prolong the half-life of IGFs, depending upon the IGF/IGFBP pair and the specific microenvironment (O'Kusky and Ye, 2012).
IGF1 is widely expressed throughout the brain throughout development (Garcia-Segura et al., 1991), and IGF1 is upregulated in neurons during the developmental periods associated with dendritic maturation and synapse formation (Bondy, 1991). Application of IGF1 to cultured cortical neurons causes an increase in puncta containing PSD-95 and synapsin, but not puncta containing gephyrin, suggestive that IGF1 treatment increases the number of excitatory rather than inhibitory synapses in the cortex (Corvin et al., 2012). Interestingly, in mice modeling a severe form of autism, Rett syndrome, treatment with an active IGF1 peptide fragment partially restores spine density, synaptic function, PSD-95 localization and levels, and synaptic plasticity (Tropea et al., 2009). IGF2 is expressed in neurons and may localize to synaptic sites, and application of IGF2 to cultured hippocampal neurons causes an increase in spine formation via an IGF2R-dependent mechanism (Schmeisser et al., 2012), in contrast to previous data suggesting that IGF2R functions only as a reservoir to bind IGF2 at the cell surface. IGF1R is found in both pre- and postsynaptic areas in certain hypothalamic nuclei and the cerebellum (Garcia-Segura et al., 1997), suggestive that IGF signaling may play roles in both pre- and postsynaptic organization. IGF2R also localizes to postsynaptic densities (Schmeisser et al., 2012).
Animal models have demonstrated the importance of IGFs in normal synaptogenesis as well as neuropsychiatric disease. In rat pups, environmental enrichment during youth is also known to reduce anxiety-like behaviors during adulthood, but this effect of environmental enrichment is lost when IGF1 activity is blocked by systemic injection of blocking peptide during environmental enrichment. Interestingly, IGF1 injection during youth mimics the anxiolytic effects of environmental enrichment when the rats reach adulthood (Baldini et al., 2013). Blockade of IGF1 during youth, and the concomitant increase in anxiety-like behaviors in adulthood, is correlated with increased hippocampal IGF1R expression at postnatal day 12 in rats and increased glucocorticoid receptor expression at postnatal day 60 (Baldini et al., 2013). Interestingly, IGF1 infusion into the CSF of adult rats improved their performance on both cognitive and affective reactivity tasks (Markowska et al., 1998).
There are limited data from humans on the potential role of IGF signaling in neuropsychiatric disease, but there are some lines of evidence that implicate IGF signaling may be important. Lithium is one of the most effective treatments available for bipolar disorder, and it is known to inhibit GSK3β (Hedgepeth et al., 1997; Chalecka-Franaszek and Chuang, 1999). In patient-derived lymphoblastoid cell lines, bipolar disorder patients who respond to lithium have higher levels of IGF1 than bipolar disorder patients who do not respond to lithium (Squassina et al., 2013). This suggests that IGF1 may act upstream of GSK3β in modulating lithium response (Cui et al., 1998; Chalecka-Franaszek and Chuang, 1999). There is also significant evidence that insulin and IGF signaling promote the aging process in many animals (Bartke, 2008; Kenyon, 2010), raising the intriguing possibility that age-related cognitive decline may be mediated by the effects of insulin and IGFs on transcription factors and synapse function.
Synaptogenic growth factor signaling pathways
There is significant crossover in the intracellular downstream signaling pathways activated by synaptogenic growth factors. These pathways include (a) the MAPK/ERK pathway, (b) the PI3K/Akt pathway, and (c) the PLC/IP3/CAMK pathway. Significantly, all of these pathways have been implicated in several different neuropsychiatric diseases. We will address the evidence linking each individual pathway to synaptogenesis and disease, and then present a model that may help explain how these systems are linked in disease pathogenesis.
The MAPK/ERK pathway
The MAPK/ERK pathway is a common signal transduction pathway for many synaptogenic growth factors, including BDNF, FGFs, some Wnts, and IGF1 (Easton et al., 1999; Perron and Bixby, 1999; Quevedo et al., 2000; Bikkavilli et al., 2008). This signaling cascade begins when a synaptogenic growth factor binds its receptor, often itself a receptor tyrosine kinase except in the case of some Wnt receptors, and activates it. This results in binding of intracellular signaling proteins, which ultimately activate MAPK, which activates ERK. ERK can activate multiple transcription factors, including CREB, RSK, and myc. There are many ways in which alterations in this signaling pathway can contribute to neuropsychiatric disease. A mutation in RSK2, one of the downstream effector molecules of this pathway, can cause Coffin-Lowry syndrome, an X-linked form of severe intellectual disability (Morice et al., 2013). Mutations of the RSK2 gene in humans are associated with smaller volumes of hippocampus, cerebellum and temporal lobe, while a mouse model of Coffin-Lowry syndrome lacking Rsk2 demonstrates defects in hippocampal spine morphology and hippocampus-dependent learning (Morice et al., 2013). There is also evidence that environmental stressors can alter the MAPK/ERK pathway. In rhesus monkeys who were abused or neglected by their mothers during childhood, decreased CSF serotonin metabolites were correlated with both activated p38 MAPK in serum monocytes as well as increased risk of anxiety behaviors, delayed social development and reduced exploration as adolescents (McCormack et al., 2006; Sanchez et al., 2007).
The PI3K/Akt pathway
Another critical intracellular signaling pathway, the PI3K/Akt pathway, is activated when synaptogenic growth factor receptors phosphorylate PI3K. PI3K activation then leads to phosphorylation of Akt. Akt can translocate into the nucleus to regulate other transcription factors, leading to changes in levels of synaptic proteins, and can also activate mTOR (mammalian target of rapamycin) and thereby indirectly influence the growth and survival of cells. In neurons, the PI3K/Akt pathway is activated by growth factors including BDNF and IGF1 (Stroppolo et al., 2001; Bondy and Cheng, 2004; Li and Thiele, 2007). One study suggests that exogenous FGF1 may activate this pathway in astrocytes (Ito et al., 2013), although whether this is also the case for neurons is unknown. There is some evidence that this pathway can be activated by FGFR2 in oligodendrocytes independent of any FGF ligand at all (Bryant et al., 2009). This pathway is also activated by FGF7 in lung tissue (Ray et al., 2003), but it is not known whether FGF7 can also activate this pathway in neurons. Environmental enrichment, which is known to have multiple beneficial effects on anxiety-like behaviors in rodents, upregulates the Akt pathway and leads to downregulation of GSK3β (Hu et al., 2013). Akt itself has been implicated as a risk factor for schizophrenia susceptibility, as a specific AKT1 haplotype causes decreased Akt levels and is associated with illness (Emamian et al., 2004). Another Akt family member, AKT3, has been shown to be important in some cases of brain malformation and epilepsy (Poduri et al., 2012b), linking this pathway to multiple aspects of brain development, including circuit formation, circuit activity, and neuronal survival. Finally, the specific serotonin reuptake inhibitor, fluoxetine, increases phosphorylation of Akt as well as ERK in rat neural stem cells (Kitagishi et al., 2012; Huang et al., 2013). The fact that fluoxetine and other medications in its class are useful for a wide variety of neuropsychiatric illnesses outside of depression lends further support to the idea that these illnesses may have common origins.
The PLC/IP3/CAMK pathway
A third common signal transduction pathway activated by many synaptogenic growth factors and implicated in neuropsychiatric disease is the PLC/IP3/CAMK pathway. It is activated by BDNF, many FGFs, and some Wnts (Klint and Claesson-Welsh, 1999; Reichardt, 2006). It may be induced by IGF1, although it is unknown whether this is via direct IGFR1 activation of PLC or if this occurs indirectly (Chattopadhyay and Carpenter, 2002). In this pathway, activation of receptor tyrosine kinases by extracellular binding of synaptogenic growth factors leads to activation of phospholipase C (PLC, most commonly PLCγ1) and generation of the second messenger IP3. IP3 diffuses to the ER where it binds to its receptor, IP3R. IP3R is a calcium channel that releases calcium from the ER. When released into the cytosol, calcium can bind to a number of calcium-dependent proteins, such as calmodulin, which activates a number of important intracellular enzymes, including the calmodulin-dependent kinases (CAMKs). CAMKs are important effector molecules for a number of neuronal functions, including long-term potentiation (Sanhueza et al., 2007) and calcium-response element (CRE)-dependent transcription (Kang et al., 2001). One particular CAMK protein, Camk2B, is expressed widely in the CNS, and levels of CAMK2B mRNA were found to be upregulated 2-fold in the frontal cortex of post-mortem schizophrenia patient brains compared to control brains (Novak et al., 2000). In a single patient, a point mutation in CAMK2G (R29P) was associated with a number of phenotypic abnormalities, including severe intellectual disability (De Ligt et al., 2012). Mice lacking Camk4 have deficits in fear learning, with corresponding reductions in phosphorylated CREB in brain areas associated with fear memory after training (Wei et al., 2002). One of the upstream signaling factors in this pathway, PLCβ1, has been implicated in severe forms of epilepsy (Kurian et al., 2010; Poduri et al., 2012a). All of these lines of evidence point to the importance of this pathway in normal neural development and function, and there is clear evidence of synaptic dysfunction and behavioral phenotypes when these pathways are altered.
Crosstalk between signaling pathways
Most synaptogenic growth factors can activate multiple downstream signaling pathways depending on which receptor they bind, and in which cell type the receptor is expressed. Due to the fact that activated growth factor receptors can bind promiscuously to various intracellular second messengers, it is unlikely that any single growth factor signaling cascade will account for all of the phenotypes observed in a given neuropsychiatric disease. It is far more likely that the complex interplay of a number of signaling pathways will generate an observable phenotype, such as autism or depression. However, all three pathways described above have intermediary signaling molecules (ERK, Akt, and CaMKII) that can activate cAMP/calcium-response element binding protein (CREB) and lead to CRE-dependent transcription of genes (Figure 3). CREB-mediated transcription is critical for expression of a number of genes, including some synaptogenic growth factors as well as c-fos and other activity-dependent genes (Benito and Barco, 2010). CREB may serve as a key integrator of signals of neuronal activity, such as NMDA receptor activation-mediated calcium influx, with synaptogenic growth factor signaling (such as the cascades described above). Activation of CREB then leads to transcription of activity-dependent genes that play roles in synaptogenesis. One such activity-dependent gene is the L-type voltage-gated calcium channel (VGCC), which has recently been the focus of much interest as SNPs within the alpha subunit of one L-type VGCC has been implicated as a risk factor in multiple neuropsychiatric diseases (Andreassen et al., 2013; Cross-Disorder Group of the Psychiatric Genomics et al., 2013).
Figure 3
Another possible cellular focus for synaptogenic growth factor signal integration is the WAVE regulatory complex (WRC), a large five-subunit complex that controls actin cytoskeleton dynamics (Pollitt and Insall, 2009). Recently, two papers were published which describe how cell surface receptors containing a WRC interacting receptor sequence (WIRS) domain interact with the WRC and the actin cytoskeleton to direct synapse formation and changes in neuronal morphology including axonal branching (Chen et al., 2014; Chia et al., 2014). Many synaptic proteins have potential WIRS domains, including some synaptogenic growth factor receptors (Chen et al., 2014). The WAVE complex might be another major intergrator of synaptogenic growth factor signaling in neurons.
Crosstalk between multiple growth factor pathways occurs as well, further underlining how interconnected these systems are in the brain. For example, Wnt signaling triggers transcription of FGF4 in tooth development (Kratochwil et al., 2002), sequential signaling by Wnt3a and FGF8 are required to induce dorsalization during brain development (Gunhaga et al., 2003), and both FGF19 and Wnt8C signaling are required for successful inner ear development (Ladher et al., 2000). Cooperative signaling of the Wnt and FGF systems is also critical in spinal cord specification (Nordstrom et al., 2006). Recently, crosstalk between FGF and Wnt signaling in C. elegans sensory organs was described on a transcriptional level, where FGF activates the MAPK/ERK pathway and regulates a downstream Wnt effector molecule (Squarzoni et al., 2011). Therefore, it will be important to consider that modulation of a single synaptogenic growth factor or intracellular signaling pathway will likely affect other systems as well.
Conclusions and future directions
Growth factor signaling between pre- and postsynaptic neurons is critical for proper connections between individual neurons, and for the development of appropriate brain circuitry. Synaptogenic growth factors play a key role in ensuring that synapses develop properly and are modulated appropriately over time, so that suitable emotional and behavioral responses to the environment are generated when necessary. As described, dysregulation of these systems may lead to inappropriate emotional and behavioral responses to either internal or external stimuli, which is associated with functional decline. Modulation of synapses over time is also critical for learning and memory when the environment changes, and dysfunction in these processes likely contributes to cognitive impairment. Ongoing synaptogenic dysregulation caused by defects in growth factor signaling may cause these illnesses not to improve (as in autism) or worsen and become increasingly difficult to treat (such as schizophrenia) over a patient's lifetime. Complicating this picture is the possibility that the specific functions of growth factors may change throughout development. Conversely, at different times throughout the life cycle, different growth factors may be required for similar functions. For example, at the neuromuscular junction (NMJ), laminin-β2 is a critical presynaptic organizer in the neonate, whereas collagen IV performs this function in the adult (Nishimune et al., 2004; Fox et al., 2007). Therefore, it is possible that the mutations or abnormalities in growth factors may only be relevant at specific developmental times, or in different locations, for specific neuropsychiatric diseases. Additionally, many other genetic risk factors for neuropsychiatric diseases are associated with synapse-specific proteins, including the synaptic scaffolding Shank proteins (Guilmatre et al., 2014), the synaptic adhesion molecules contactin/caspr and neurexin/neuroligin (Sudhof, 2008; Vernes et al., 2008; Kenny et al., 2013; Zuko et al., 2013), and proteins in the mTOR pathway, which is critical for synapse-specific protein synthesis (Hoeffer and Klann, 2010; Russo et al., 2012; Wong, 2013). These molecules and pathways may interact with the growth factor pathways (Patzke and Ernsberger, 2000; Iki et al., 2005; Hoeffer and Klann, 2010; Williams and Casanova, 2011; Russo et al., 2012; Wong, 2013; Bennett and Lagopoulos, 2014). The myriad ways in which these pathways may be linked requires further exploration.
Nevertheless, since many receptors for synaptogenic growth factors act through common intracellular signal transduction pathways, it may be that modulation of one or a few of these pathways could lead to significant resolution of clinical symptoms. In addition, growth factor binding proteins often act as regulators of growth factor binding and localization, which have the added benefit of functioning in the extracellular space rather than intracellular compartments. This could significantly reduce the difficulty of getting treatments to their target sites. Additionally, in the case of FGFs, heparan sulfate proteoglycans (HSPGs) are required for binding of FGFs to their receptors at high affinity (Klint and Claesson-Welsh, 1999). Modulation of certain HSPGs could alter FGF binding to particular FGFRs. Such an approach may also be possible with other synaptogenic growth factors.
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 potential conflict of interest.
Statements
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
AdesL. C.SullivanK.BigginA.HaanE. A.BrettM.HolmanK. J.et al. (2006). FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited. Am. J. Med. Genet. A140, 1047–1058. 10.1002/ajmg.a.31202
2
Agis-BalboaR. C.Arcos-DiazD.WittnamJ.GovindarajanN.BlomK.BurkhardtS.et al. (2011). A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories. EMBO J. 30, 4071–4083. 10.1038/emboj.2011.293
3
Ahmad-AnnuarA.CianiL.SimeonidisI.HerrerosJ.FredjN. B.RossoS. B.et al. (2006). Signaling across the synapse: a role for Wnt and Dishevelled in presynaptic assembly and neurotransmitter release. J. Cell Biol. 174, 127–139. 10.1083/jcb.200511054
4
AliashkevichA. F.Yilmazer-HankeD.Van RoostD.MundhenkB.SchrammJ.BlumckeI. (2003). Cellular pathology of amygdala neurons in human temporal lobe epilepsy. Acta Neuropathol. 106, 99–106. 10.1007/s00401-003-0707-0
5
AlsmadiO.MeyerB. F.AlkurayaF.WakilS.AlkayalF.Al-SaudH.et al. (2009). Syndromic congenital sensorineural deafness, microtia and microdontia resulting from a novel homoallelic mutation in fibroblast growth factor 3 (FGF3). Eur. J. Hum. Genet. 17, 14–21. 10.1038/ejhg.2008.141
6
AndreassenO. A.DjurovicS.ThompsonW. K.SchorkA. J.KendlerK. S.O'donovanM. C.et al. (2013). Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors. Am. J. Hum. Genet. 92, 197–209. 10.1016/j.ajhg.2013.01.001
7
ArauzR. F.SolomonB. D.Pineda-AlvarezD. E.GropmanA. L.ParsonsJ. A.RoesslerE.et al. (2010). A hypomorphic allele in the FGF8 gene contributes to holoprosencephaly and is allelic to gonadotropin-releasing hormone deficiency in humans. Mol. Syndromol. 1, 59–66. 10.1159/000302285
8
ArnaldezF. I.HelmanL. J. (2012). Targeting the insulin growth factor receptor 1. Hematol. Oncol. Clin. North Am. 26, 527–542, vii–viii. 10.1016/j.hoc.2012.01.004
9
AssociationA. P. (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th Edn. Arlington, VA: American Psychiatric Publishing.
10
BabicM.ZinsmaierK. E. (2011). Memory, synapse stability, and beta-adducin. Neuron69, 1039–1041. 10.1016/j.neuron.2011.03.004
11
BaldiniS.RestaniL.BaroncelliL.ColtelliM.FrancoR.CenniM. C.et al. (2013). Enriched early life experiences reduce adult anxiety-like behavior in rats: a role for insulin-like growth factor 1. J. Neurosci. 33, 11715–11723. 10.1523/JNEUROSCI.3541-12.2013
12
BarrosC. S.CalabreseB.ChameroP.RobertsA. J.KorzusE.LloydK.et al. (2009). Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system. Proc. Natl. Acad. Sci. U.S.A. 106, 4507–4512. 10.1073/pnas.0900355106
13
BartkeA. (2008). Insulin and aging. Cell Cycle7, 3338–3343. 10.4161/cc.7.21.7012
14
BeenkenA.MohammadiM. (2009). The FGF family: biology, pathophysiology and therapy. Nat. Rev. Drug Discov. 8, 235–253. 10.1038/nrd2792
15
BendallS. C.StewartM. H.MenendezP.GeorgeD.VijayaragavanK.Werbowetski-OgilvieT.et al. (2007). IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature448, 1015–1021. 10.1038/nature06027
16
BenitoE.BarcoA. (2010). CREB's control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models. Trends Neurosci. 33, 230–240. 10.1016/j.tins.2010.02.001
17
BennettM. R.LagopoulosJ. (2014). Stress and trauma: BDNF control of dendritic-spine formation and regression. Prog. Neurobiol. 112, 80–99. 10.1016/j.pneurobio.2013.10.005
18
BikkavilliR. K.FeiginM. E.MalbonC. C. (2008). p38 mitogen-activated protein kinase regulates canonical Wnt-beta-catenin signaling by inactivation of GSK3beta. J. Cell Sci. 121, 3598–3607. 10.1242/jcs.032854
19
BlakelyB. D.ByeC. R.FernandoC. V.PrasadA. A.PasterkampR. J.MachedaM. L.et al. (2013). Ryk, a receptor regulating Wnt5a-mediated neurogenesis and axon morphogenesis of ventral midbrain dopaminergic neurons. Stem Cells Dev. 22, 2132–2144. 10.1089/scd.2013.0066
20
BondyC. A. (1991). Transient IGF-I gene expression during the maturation of functionally related central projection neurons. J. Neurosci. 11, 3442–3455.
21
BondyC. A.ChengC. M. (2004). Signaling by insulin-like growth factor 1 in brain. Eur. J. Pharmacol. 490, 25–31. 10.1016/j.ejphar.2004.02.042
22
BookoutA. L.De GrootM. H.OwenB. M.LeeS.GautronL.LawrenceH. L.et al. (2013). FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat. Med. 19, 1147–1152. 10.1038/nm.3249
23
BoucherT. J.OkuseK.BennettD. L.MunsonJ. B.WoodJ. N.McMahonS. B. (2000). Potent analgesic effects of GDNF in neuropathic pain states. Science290, 124–127. 10.1126/science.290.5489.124
24
BrennandK. J.SimoneA.JouJ.Gelboin-BurkhartC.TranN.SangarS.et al. (2011). Modelling schizophrenia using human induced pluripotent stem cells. Nature473, 221–225. 10.1038/nature09915
25
BrionneT. C.TesseurI.MasliahE.Wyss-CorayT. (2003). Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron40, 1133–1145. 10.1016/S0896-6273(03)00766-9
26
BryantM. R.MartaC. B.KimF. S.BansalR. (2009). Phosphorylation and lipid raft association of fibroblast growth factor receptor-2 in oligodendrocytes. Glia57, 935–946. 10.1002/glia.20818
27
BulowB.HagmarL.OrbaekP.OsterbergK.ErfurthE. M. (2002). High incidence of mental disorders, reduced mental well-being and cognitive function in hypopituitary women with GH deficiency treated for pituitary disease. Clin. Endocrinol. (Oxf.)56, 183–193. 10.1046/j.0300-0664.2001.01461.x
28
CaoL.JiaoX.ZuzgaD. S.LiuY.FongD. M.YoungD.et al. (2004). VEGF links hippocampal activity with neurogenesis, learning and memory. Nat. Genet. 36, 827–835. 10.1038/ng1395
29
CarnicellaS.KharaziaV.JeanblancJ.JanakP. H.RonD. (2008). GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse. Proc. Natl. Acad. Sci. U.S.A. 105, 8114–8119. 10.1073/pnas.0711755105
30
CarvalhoO. P.ThorntonG. K.HertecantJ.HouldenH.NicholasA. K.CoxJ. J.et al. (2011). A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy. J. Med. Genet. 48, 131–135. 10.1136/jmg.2010.081455
31
Chalecka-FranaszekE.ChuangD. M. (1999). Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc. Natl. Acad. Sci. U.S.A. 96, 8745–8750.
32
ChattopadhyayA.CarpenterG. (2002). PLC-gamma1 is required for IGF-I protection from cell death induced by loss of extracellular matrix adhesion. J. Cell Sci. 115, 2233–2239.
33
ChenB.BrinkmannK.ChenZ.PakC. W.LiaoY.ShiS.et al. (2014). The WAVE regulatory complex links diverse receptors to the actin cytoskeleton. Cell156, 195–207. 10.1016/j.cell.2013.11.048
34
ChenD. Y.SternS. A.Garcia-OstaA.Saunier-ReboriB.PolloniniG.Bambah-MukkuD.et al. (2011). A critical role for IGF-II in memory consolidation and enhancement. Nature469, 491–497. 10.1038/nature09667
35
ChenJ.ParkC. S.TangS. J. (2006a). Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation. J. Biol. Chem. 281, 11910–11916. 10.1074/jbc.M511920200
36
ChenZ. Y.JingD.BathK. G.IeraciA.KhanT.SiaoC. J.et al. (2006b). Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science314, 140–143. 10.1126/science.1129663
37
ChiaP. H.ChenB.LiP.RosenM. K.ShenK. (2014). Local F-actin network links synapse formation and axon branching. Cell156, 208–220. 10.1016/j.cell.2013.12.009
38
CholfinJ. A.RubensteinJ. L. (2007). Patterning of frontal cortex subdivisions by Fgf17. Proc. Natl. Acad. Sci. U.S.A. 104, 7652–7657. 10.1073/pnas.0702225104
39
ChungK.WallaceJ.KimS. Y.KalyanasundaramS.AndalmanA. S.DavidsonT. J.et al. (2013). Structural and molecular interrogation of intact biological systems. Nature497, 332–337. 10.1038/nature12107
40
CianiL.BoyleK. A.DickinsE.SahoresM.AnaneD.LopesD. M.et al. (2011). Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca(2)(+)/Calmodulin-dependent protein kinase II. Proc. Natl. Acad. Sci. U.S.A. 108, 10732–10737. 10.1073/pnas.1018132108
41
ClarimonJ.XiromerisiouG.EerolaJ.GourbaliV.HellstromO.DardiotisE.et al. (2005). Lack of evidence for a genetic association between FGF20 and Parkinson's disease in Finnish and Greek patients. BMC Neurol. 5:11. 10.1186/1471-2377-5-11
42
ColvinJ. S.BohneB. A.HardingG. W.McEwenD. G.OrnitzD. M. (1996). Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat. Genet. 12, 390–397. 10.1038/ng0496-390
43
CorvinA. P.MolinosI.LittleG.DonohoeG.GillM.MorrisD. W.et al. (2012). Insulin-like growth factor 1 (IGF1) and its active peptide (1-3)IGF1 enhance the expression of synaptic markers in neuronal circuits through different cellular mechanisms. Neurosci. Lett. 520, 51–56. 10.1016/j.neulet.2012.05.029
44
CosgayaJ. M.ChanJ. R.ShooterE. M. (2002). The neurotrophin receptor p75NTR as a positive modulator of myelination. Science298, 1245–1248. 10.1126/science.1076595
45
CountsS. E.NadeemM.WuuJ.GinsbergS. D.SaragoviH. U.MufsonE. J. (2004). Reduction of cortical TrkA but not p75(NTR) protein in early-stage Alzheimer's disease. Ann. Neurol. 56, 520–531. 10.1002/ana.20233
46
Cross-Disorder Group of the PsychiatricGenomicsC.SmollerJ. W.CraddockN.KendlerK.LeeP. H.NealeB. M.et al. (2013). Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet381, 1371–1379. 10.1016/S0140-6736(12)62129-1
47
CuiH.MengY.BulleitR. F. (1998). Inhibition of glycogen synthase kinase 3beta activity regulates proliferation of cultured cerebellar granule cells. Brain Res. Dev. Brain Res. 111, 177–188.
48
DavisE. K.ZouY.GhoshA. (2008). Wnts acting through canonical and noncanonical signaling pathways exert opposite effects on hippocampal synapse formation. Neural Dev. 3, 32. 10.1186/1749-8104-3-32
49
DeA. (2011). Wnt/Ca2+ signaling pathway: a brief overview. Acta Biochim. Biophys. Sin. (Shanghai). 43, 745–756. 10.1093/abbs/gmr079
50
De LigtJ.WillemsenM. H.Van BonB. W.KleefstraT.YntemaH. G.KroesT.et al. (2012). Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929. 10.1056/NEJMoa1206524
51
DodeC.LevilliersJ.DupontJ. M.De PaepeA.Le DuN.Soussi-YanicostasN.et al. (2003). Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat. Genet. 33, 463–465. 10.1038/ng1122
52
DoniachT. (1995). Basic FGF as an inducer of anteroposterior neural pattern. Cell83, 1067–1070.
53
DonoR. (2003). Fibroblast growth factors as regulators of central nervous system development and function. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R867–R881. 10.1152/ajpregu.00533.2002
54
DonoR.TexidoG.DusselR.EhmkeH.ZellerR. (1998). Impaired cerebral cortex development and blood pressure regulation in FGF-2-deficient mice. EMBO J. 17, 4213–4225. 10.1093/emboj/17.15.4213
55
EastonJ. B.MoodyN. M.ZhuX.MiddlemasD. S. (1999). Brain-derived neurotrophic factor induces phosphorylation of fibroblast growth factor receptor substrate 2. J. Biol. Chem. 274, 11321–11327.
56
EganM. F.KojimaM.CallicottJ. H.GoldbergT. E.KolachanaB. S.BertolinoA.et al. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell112, 257–269. 10.1016/S0092-8674(03)00035-7
57
EmamianE. S.HallD.BirnbaumM. J.KarayiorgouM.GogosJ. A. (2004). Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat. Genet. 36, 131–137. 10.1038/ng1296
58
Eren-KocakE.TurnerC. A.WatsonS. J.AkilH. (2011). Short-hairpin RNA silencing of endogenous fibroblast growth factor 2 in rat hippocampus increases anxiety behavior. Biol. Psychiatry69, 534–540. 10.1016/j.biopsych.2010.11.020
59
EvansS. J.ChoudaryP. V.NealC. R.LiJ. Z.VawterM. P.TomitaH.et al. (2004). Dysregulation of the fibroblast growth factor system in major depression. Proc. Natl. Acad. Sci. U.S.A. 101, 15506–15511. 10.1073/pnas.0406788101
60
FaganA. M.GarberM.BarbacidM.Silos-SantiagoI.HoltzmanD. M. (1997). A role for TrkA during maturation of striatal and basal forebrain cholinergic neurons in vivo. J. Neurosci. 17, 7644–7654.
61
FalardeauJ.ChungW. C.BeenkenA.RaivioT.PlummerL.SidisY.et al. (2008). Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J. Clin. Invest. 118, 2822–2831. 10.1172/JCI34538
62
FarhadiH. F.MowlaS. J.PetreccaK.MorrisS. J.SeidahN. G.MurphyR. A. (2000). Neurotrophin-3 sorts to the constitutive secretory pathway of hippocampal neurons and is diverted to the regulated secretory pathway by coexpression with brain-derived neurotrophic factor. J. Neurosci. 20, 4059–4068.
63
FernandezA. M.Torres-AlemanI. (2012). The many faces of insulin-like peptide signalling in the brain. Nat. Rev. Neurosci. 13, 225–239. 10.1038/nrn3209
64
FiorentinoH.KuczewskiN.DiabiraD.FerrandN.PangalosM. N.PorcherC.et al. (2009). GABA(B) receptor activation triggers BDNF release and promotes the maturation of GABAergic synapses. J. Neurosci. 29, 11650–11661. 10.1523/JNEUROSCI.3587-09.2009
65
FlajoletM.WangZ.FutterM.ShenW.NuangchamnongN.BendorJ.et al. (2008). FGF acts as a co-transmitter through adenosine A(2A) receptor to regulate synaptic plasticity. Nat. Neurosci. 11, 1402–1409. 10.1038/nn.2216
66
FortressA. M.SchramS. L.TuscherJ. J.FrickK. M. (2013). Canonical Wnt signaling is necessary for object recognition memory consolidation. J. Neurosci. 33, 12619–12626. 10.1523/JNEUROSCI.0659-13.2013
67
FoxM. A.SanesJ. R.BorzaD. B.EswarakumarV. P.FasslerR.HudsonB. G.et al. (2007). Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals. Cell129, 179–193. 10.1016/j.cell.2007.02.035
68
FrancomanoC. A.McIntoshI.WilkinD. J. (1996). Bone dysplasias in man: molecular insights. Curr. Opin. Genet. Dev. 6, 301–308.
69
FrenzD. A.LiuW.CveklA.XieQ.WassefL.QuadroL.et al. (2010). Retinoid signaling in inner ear development: a “Goldilocks” phenomenon. Am. J. Med. Genet. A152A, 2947–2961. 10.1002/ajmg.a.33670
70
Fukuchi-ShimogoriT.GroveE. A. (2001). Neocortex patterning by the secreted signaling molecule FGF8. Science294, 1071–1074. 10.1126/science.1064252
71
Garcia-SeguraL. M.PerezJ.PonsS.RejasM. T.Torres-AlemanI. (1991). Localization of insulin-like growth factor I (IGF-I)-like immunoreactivity in the developing and adult rat brain. Brain Res. 560, 167–174.
72
Garcia-SeguraL. M.RodriguezJ. R.Torres-AlemanI. (1997). Localization of the insulin-like growth factor I receptor in the cerebellum and hypothalamus of adult rats: an electron microscopic study. J. Neurocytol. 26, 479–490.
73
Garcia-VargasA.HafnerC.Perez-RodriguezA. G.Rodriguez-RojasL. X.Gonzalez-EsquedaP.StoehrR.et al. (2008). An epidermal nevus syndrome with cerebral involvement caused by a mosaic FGFR3 mutation. Am. J. Med. Genet. A146A, 2275–2279. 10.1002/ajmg.a.32429
74
GellerB.BadnerJ. A.TillmanR.ChristianS. L.BolhofnerK.CookE. H.Jr. (2004). Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. Am. J. Psychiatry161, 1698–1700. 10.1176/appi.ajp.161.9.1698
75
GiganteA. D.YoungL. T.YathamL. N.AndreazzaA. C.NeryF. G.GrinbergL. T.et al. (2011). Morphometric post-mortem studies in bipolar disorder: possible association with oxidative stress and apoptosis. Int. J. Neuropsychopharmacol. 14, 1075–1089. 10.1017/S146114571000146X
76
GogollaN.GalimbertiI.DeguchiY.CaroniP. (2009). Wnt signaling mediates experience-related regulation of synapse numbers and mossy fiber connectivities in the adult hippocampus. Neuron62, 510–525. 10.1016/j.neuron.2009.04.022
77
GouldT. D.O'donnellK. C.PicchiniA. M.DowE. R.ChenG.ManjiH. K. (2008). Generation and behavioral characterization of beta-catenin forebrain-specific conditional knock-out mice. Behav. Brain Res. 189, 117–125. 10.1016/j.bbr.2007.12.028
78
GrippK. W.StolleC. A.McDonald-McGinnD. M.MarkowitzR. I.BartlettS. P.KatowitzJ. A.et al. (1998). Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III. Am. J. Med. Genet. 78, 356–360.
79
GuillemotF.ZimmerC. (2011). From cradle to grave: the multiple roles of fibroblast growth factors in neural development. Neuron71, 574–588. 10.1016/j.neuron.2011.08.002
80
GuilmatreA.HuguetG.DelormeR.BourgeronT. (2014). The emerging role of SHANK genes in neuropsychiatric disorders. Dev. Neurobiol. 74, 113–122. 10.1002/dneu.22128
81
GunhagaL.MarklundM.SjodalM.HsiehJ. C.JessellT. M.EdlundT. (2003). Specification of dorsal telencephalic character by sequential Wnt and FGF signaling. Nat. Neurosci. 6, 701–707. 10.1038/nn1068
82
HallA. C.BrennanA.GooldR. G.CleverleyK.LucasF. R.Gordon-WeeksP. R.et al. (2002). Valproate regulates GSK-3-mediated axonal remodeling and synapsin I clustering in developing neurons. Mol. Cell. Neurosci. 20, 257–270. 10.1006/mcne.2002.1117
83
HallA. C.LucasF. R.SalinasP. C. (2000). Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell100, 525–535. 10.1016/S0092-8674(00)80689-3
84
HallD.DhillaA.CharalambousA.GogosJ. A.KarayiorgouM. (2003). Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. Am. J. Hum. Genet. 73, 370–376. 10.1086/377003
85
HanJ. C.LiuQ. R.JonesM.LevinnR. L.MenzieC. M.Jefferson-GeorgeK. S.et al. (2008). Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N. Engl. J. Med. 359, 918–927. 10.1056/NEJMoa0801119
86
HedgepethC. M.ConradL. J.ZhangJ.HuangH. C.LeeV. M.KleinP. S. (1997). Activation of the Wnt signaling pathway: a molecular mechanism for lithium action. Dev. Biol. 185, 82–91. 10.1006/dbio.1997.8552
87
HenslerJ. G.LadenheimE. E.LyonsW. E. (2003). Ethanol consumption and serotonin-1A (5-HT1A) receptor function in heterozygous BDNF (+/-) mice. J. Neurochem. 85, 1139–1147. 10.1046/j.1471-4159.2003.01748.x
88
HoefferC. A.KlannE. (2010). mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33, 67–75. 10.1016/j.tins.2009.11.003
89
HollwayG. E.SuthersG. K.BatteseK. M.TurnerA. M.DavidD. J.MulleyJ. C. (1998). Deafness due to Pro250Arg mutation of FGFR3. Lancet351, 877–878. 10.1016/S0140-6736(98)24012-8
90
HongE. J.McCordA. E.GreenbergM. E. (2008). A biological function for the neuronal activity-dependent component of Bdnf transcription in the development of cortical inhibition. Neuron60, 610–624. 10.1016/j.neuron.2008.09.024
91
HouartC.CaneparoL.HeisenbergC.BarthK.Take-UchiM.WilsonS. (2002). Establishment of the telencephalon during gastrulation by local antagonism of Wnt signaling. Neuron35, 255–265. 10.1016/S0896-6273(02)00751-1
92
HuY. S.LongN.PiginoG.BradyS. T.LazarovO. (2013). Molecular mechanisms of environmental enrichment: impairments in Akt/GSK3beta, neurotrophin-3 and CREB signaling. PLoS ONE8:e64460. 10.1371/journal.pone.0064460
93
HuangW.ZhaoY.ZhuX.CaiZ.WangS.YaoS.et al. (2013). Fluoxetine upregulates phosphorylated-AKT and phosphorylated-ERK1/2 proteins in neural stem cells: evidence for a crosstalk between AKT and ERK1/2 pathways. J. Mol. Neurosci. 49, 244–249. 10.1007/s12031-012-9822-5
94
IkiJ.InoueA.BitoH.OkabeS. (2005). Bi-directional regulation of postsynaptic cortactin distribution by BDNF and NMDA receptor activity. Eur. J. Neurosci. 22, 2985–2994. 10.1111/j.1460-9568.2005.04510.x
95
IrvingC.MalhasA.GuthrieS.MasonI. (2002). Establishing the trochlear motor axon trajectory: role of the isthmic organiser and Fgf8. Development129, 5389–5398. 10.1242/dev.00117
96
IssaG.WilsonC.TerryA. V.Jr.PillaiA. (2010). An inverse relationship between cortisol and BDNF levels in schizophrenia: data from human postmortem and animal studies. Neurobiol. Dis. 39, 327–333. 10.1016/j.nbd.2010.04.017
97
ItamiC.MizunoK.KohnoT.NakamuraS. (2000). Brain-derived neurotrophic factor requirement for activity-dependent maturation of glutamatergic synapse in developing mouse somatosensory cortex. Brain Res. 857, 141–150. 10.1016/S0006-8993(99)02352-5
98
ItoJ.NagayasuY.HoshikawaM.KatoK. H.MiuraY.AsaiK.et al. (2013). Enhancement of FGF-1 release along with cytosolic proteins from rat astrocytes by hydrogen peroxide. Brain Res. 1522, 12–21. 10.1016/j.brainres.2013.05.035
99
JeanblancJ.HeD. Y.McGoughN. N.LogripM. L.PhamluongK.JanakP. H.et al. (2006). The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption. J. Neurosci. 26, 1457–1464. 10.1523/JNEUROSCI.3786-05.2006
100
JeffersM.ShimketsR.PrayagaS.BoldogF.YangM.BurgessC.et al. (2001). Identification of a novel human fibroblast growth factor and characterization of its role in oncogenesis. Cancer Res. 61, 3131–3138.
101
JohnsonE. M.CraigE. T.YehH. H. (2007). TrkB is necessary for pruning at the climbing fibre-Purkinje cell synapse in the developing murine cerebellum. J. Physiol. 582, 629–646. 10.1113/jphysiol.2007.133561
102
Johnson-VenkateshE. M.UmemoriH. (2010). Secreted factors as synaptic organizers. Eur. J. Neurosci. 32, 181–190. 10.1111/j.1460-9568.2010.07338.x
103
KangH.SunL. D.AtkinsC. M.SoderlingT. R.WilsonM. A.TonegawaS. (2001). An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory. Cell106, 771–783. 10.1016/S0092-8674(01)00497-4
104
KennyE. M.CormicanP.FurlongS.HeronE.KennyG.FaheyC.et al. (2013). Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders. Mol. Psychiatry. [Epub ahead of print]. 10.1038/mp.2013.127
105
KenyonC. J. (2010). The genetics of ageing. Nature464, 504–512. 10.1038/nature08980
106
KimH.WonS.HwangD. Y.LeeJ. S.KimM.KimR.et al. (2011). Downregulation of Wnt/beta-catenin signaling causes degeneration of hippocampal neurons in vivo. Neurobiol. Aging32, 2316.e1–2316.e15. 10.1016/j.neurobiolaging.2010.03.013
107
KitagishiY.KobayashiM.KikutaK.MatsudaS. (2012). Roles of PI3K/AKT/GSK3/mTOR pathway in cell signaling of mental illnesses. Depress. Res. Treat. 2012:752563. 10.1155/2012/752563
108
KlintP.Claesson-WelshL. (1999). Signal transduction by fibroblast growth factor receptors. Front. Biosci. 4, D165–D177. 10.2741/Klint
109
KramerA.YangF. C.SnodgrassP.LiX.ScammellT. E.DavisF. C.et al. (2001). Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science294, 2511–2515. 10.1126/science.1067716
110
KratochwilK.GalceranJ.TontschS.RothW.GrosschedlR. (2002). FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. Genes Dev. 16, 3173–3185. 10.1101/gad.1035602
111
KrieglsteinK.ZhengF.UnsickerK.AlzheimerC. (2011). More than being protective: functional roles for TGF-beta/activin signaling pathways at central synapses. Trends Neurosci. 34, 421–429. 10.1016/j.tins.2011.06.002
112
KrylovaO.HerrerosJ.CleverleyK. E.EhlerE.HenriquezJ. P.HughesS. M.et al. (2002). WNT-3, expressed by motoneurons, regulates terminal arborization of neurotrophin-3-responsive spinal sensory neurons. Neuron35, 1043–1056. 10.1016/S0896-6273(02)00860-7
113
KurianM. A.MeyerE.VassalloG.MorganN. V.PrakashN.PashaS.et al. (2010). Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain133, 2964–2970. 10.1093/brain/awq238
114
LadherR. K.AnakweK. U.GurneyA. L.SchoenwolfG. C.Francis-WestP. H. (2000). Identification of synergistic signals initiating inner ear development. Science290, 1965–1967. 10.1126/science.290.5498.1965
115
LaiK. O.WongA. S.CheungM. C.XuP.LiangZ.LokK. C.et al. (2012). TrkB phosphorylation by Cdk5 is required for activity-dependent structural plasticity and spatial memory. Nat. Neurosci. 15, 1506–1515. 10.1038/nn.3237
116
LakoM.LindsayS.BullenP.WilsonD. I.RobsonS. C.StrachanT. (1998). A novel mammalian wnt gene, WNT8B, shows brain-restricted expression in early development, with sharply delimited expression boundaries in the developing forebrain. Hum. Mol. Genet. 7, 813–822.
117
LarimoreJ. L.ChapleauC. A.KudoS.TheibertA.PercyA. K.Pozzo-MillerL. (2009). Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations. Neurobiol. Dis. 34, 199–211. 10.1016/j.nbd.2008.12.011
118
LeeC. H.JavedD.AlthausA. L.ParentJ. M.UmemoriH. (2012). Neurogenesis is enhanced and mossy fiber sprouting arises in FGF7-deficient mice during development. Mol. Cell. Neurosci. 51, 61–67. 10.1016/j.mcn.2012.07.010
119
LeeC. H.UmemoriH. (2013). Suppression of epileptogenesis-associated changes in response to seizures in FGF22-deficient mice. Front. Cell. Neurosci. 7:43. 10.3389/fncel.2013.00043
120
Le-NiculescuH.PatelS. D.BhatM.KuczenskiR.FaraoneS. V.TsuangM. T.et al. (2009). Convergent functional genomics of genome-wide association data for bipolar disorder: comprehensive identification of candidate genes, pathways and mechanisms. Am. J. Med. Genet. B Neuropsychiatr. Genet. 150B, 155–181. 10.1002/ajmg.b.30887
121
Levi-MontalciniR. (1987). The nerve growth factor 35 years later. Science237, 1154–1162.
122
LiA. J.SuzukiS.SuzukiM.MizukoshiE.ImamuraT. (2002). Fibroblast growth factor-2 increases functional excitatory synapses on hippocampal neurons. Eur. J. Neurosci. 16, 1313–1324. 10.1046/j.1460-9568.2002.02193.x
123
LiE.KimD. H.CaiM.LeeS.KimY.LimE.et al. (2011). Hippocampus-dependent spatial learning and memory are impaired in growth hormone-deficient spontaneous dwarf rats. Endocr. J. 58, 257–267. 10.1507/endocrj.K11E-006
124
LiZ.ThieleC. J. (2007). Targeting Akt to increase the sensitivity of neuroblastoma to chemotherapy: lessons learned from the brain-derived neurotrophic factor/TrkB signal transduction pathway. Expert Opin. Ther. Targets11, 1611–1621. 10.1517/14728222.11.12.1611
125
LichtensteinP.CarlstromE.RastamM.GillbergC.AnckarsaterH. (2010). The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am. J. Psychiatry167, 1357–1363. 10.1176/appi.ajp.2010.10020223
126
LieD. C.ColamarinoS. A.SongH. J.DesireL.MiraH.ConsiglioA.et al. (2005). Wnt signalling regulates adult hippocampal neurogenesis. Nature437, 1370–1375. 10.1038/nature04108
127
LijamN.PaylorR.McDonaldM. P.CrawleyJ. N.DengC. X.HerrupK.et al. (1997). Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1. Cell90, 895–905.
128
LilleyB. N.PanY. A.SanesJ. R. (2013). SAD kinases sculpt axonal arbors of sensory neurons through long- and short-term responses to neurotrophin signals. Neuron79, 39–53. 10.1016/j.neuron.2013.05.017
129
LinT.SanduskyS. B.XueH.FishbeinK. W.SpencerR. G.RaoM. S.et al. (2003). A central nervous system specific mouse model for thanatophoric dysplasia type II. Hum. Mol. Genet. 12, 2863–2871. 10.1093/hmg/ddg309
130
LiuG.GuB.HeX. P.JoshiR. B.WackerleH. D.RodriguizR. M.et al. (2013). Transient inhibition of TrkB kinase after status epilepticus prevents development of temporal lobe epilepsy. Neuron79, 31–38. 10.1016/j.neuron.2013.04.027
131
LiuR. J.LeeF. S.LiX. Y.BambicoF.DumanR. S.AghajanianG. K. (2012). Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol. Psychiatry71, 996–1005. 10.1016/j.biopsych.2011.09.030
132
LiuX.ErnforsP.WuH.JaenischR. (1995). Sensory but not motor neuron deficits in mice lacking NT4 and BDNF. Nature375, 238–241. 10.1038/375238a0
133
LoeysB. L.ChenJ.NeptuneE. R.JudgeD. P.PodowskiM.HolmT.et al. (2005). A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet. 37, 275–281. 10.1038/ng1511
134
LogueM. W.BaldwinC.GuffantiG.MelistaE.WolfE. J.ReardonA. F.et al. (2013). A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus. Mol. Psychiatry18, 937–942. 10.1038/mp.2012.113
135
LucasF. R.SalinasP. C. (1997). WNT-7a induces axonal remodeling and increases synapsin I levels in cerebellar neurons. Dev. Biol. 192, 31–44. 10.1006/dbio.1997.8734
136
LynchC. J.UddinL. Q.SupekarK.KhouzamA.PhillipsJ.MenonV. (2013). Default mode network in childhood autism: posteromedial cortex heterogeneity and relationship with social deficits. Biol. Psychiatry74, 212–219. 10.1016/j.biopsych.2012.12.013
137
LyonsW. E.MamounasL. A.RicaurteG. A.CoppolaV.ReidS. W.BoraS. H.et al. (1999). Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc. Natl. Acad. Sci. U.S.A. 96, 15239–15244.
138
MaL.HaradaT.HaradaC.RomeroM.HebertJ. M.McConnellS. K.et al. (2002). Neurotrophin-3 is required for appropriate establishment of thalamocortical connections. Neuron36, 623–634. 10.1016/S0896-6273(02)01021-8
139
MacleodR. J.MooresM. E.BeningerR. J. (2012). Amphetamine stimulates Wnt3 increases in rat nucleus accumbens. Neuroreport23, 846–850. 10.1097/WNR.0b013e328357d868
140
ManjiH. K.DrevetsW. C.CharneyD. S. (2001). The cellular neurobiology of depression. Nat. Med. 7, 541–547. 10.1038/87865
141
MardyS.MiuraY.EndoF.MatsudaI.SztrihaL.FrossardP.et al. (1999). Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor. Am. J. Hum. Genet. 64, 1570–1579. 10.1086/302422
142
MargolisR. L.ChuangD. M.PostR. M. (1994). Programmed cell death: implications for neuropsychiatric disorders. Biol. Psychiatry35, 946–956.
143
MarkowskaA. L.MooneyM.SonntagW. E. (1998). Insulin-like growth factor-1 ameliorates age-related behavioral deficits. Neuroscience87, 559–569.
144
MartinD. J.SmithD. J. (2013). Is there a clinical prodrome of bipolar disorder? A review of the evidence. Expert Rev. Neurother. 13, 89–98. 10.1586/ern.12.149
145
Martinez-MoralesJ. R.Del BeneF.NicaG.HammerschmidtM.BovolentaP.WittbrodtJ. (2005). Differentiation of the vertebrate retina is coordinated by an FGF signaling center. Dev. Cell8, 565–574. 10.1016/j.devcel.2005.01.022
146
MasonI. (2007). Initiation to end point: the multiple roles of fibroblast growth factors in neural development. Nat. Rev. Neurosci. 8, 583–596. 10.1038/nrn2189
147
MauceriD.FreitagH. E.OliveiraA. M.BengtsonC. P.BadingH. (2011). Nuclear calcium-VEGFD signaling controls maintenance of dendrite arborization necessary for memory formation. Neuron71, 117–130. 10.1016/j.neuron.2011.04.022
148
McCormackK.SanchezM. M.BardiM.MaestripieriD. (2006). Maternal care patterns and behavioral development of rhesus macaque abused infants in the first 6 months of life. Dev. Psychobiol. 48, 537–550. 10.1002/dev.20157
149
McCoyP. A.ShaoY.WolpertC. M.DonnellyS. L.Ashley-KochA.AbelH. L.et al. (2002). No association between the WNT2 gene and autistic disorder. Am. J. Med. Genet. 114, 106–109. 10.1002/ajmg.10182
150
McFarlaneS.McNeillL.HoltC. E. (1995). FGF signaling and target recognition in the developing Xenopus visual system. Neuron15, 1017–1028.
151
McGoughN. N.HeD. Y.LogripM. L.JeanblancJ.PhamluongK.LuongK.et al. (2004). RACK1 and brain-derived neurotrophic factor: a homeostatic pathway that regulates alcohol addiction. J. Neurosci. 24, 10542–10552. 10.1523/JNEUROSCI.3714-04.2004
152
McGrathC. L.GlattS. J.SklarP.Le-NiculescuH.KuczenskiR.DoyleA. E.et al. (2009). Evidence for genetic association of RORB with bipolar disorder. BMC Psychiatry9:70. 10.1186/1471-244X-9-70
153
MeiL.XiongW. C. (2008). Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat. Rev. Neurosci. 9, 437–452. 10.1038/nrn2392
154
MennerickS.ZorumskiC. F. (2000). Neural activity and survival in the developing nervous system. Mol. Neurobiol. 22, 41–54. 10.1385/MN:22:1-3:041
155
MesserC. J.EischA. J.CarlezonW. A.Jr.WhislerK.ShenL.WolfD. H.et al. (2000). Role for GDNF in biochemical and behavioral adaptations to drugs of abuse. Neuron26, 247–257. 10.1016/S0896-6273(00)81154-X
156
MeyerR. M.Burgos-RoblesA.LiuE.CorreiaS. S.GoosensK. A. (2013). A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear. Mol. Psychiatry. [Epub ahead of print]. 10.1038/mp.2013.135
157
Meyer-FrankeA.KaplanM. R.PfriegerF. W.BarresB. A. (1995). Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron15, 805–819.
158
MeyersE. N.LewandoskiM.MartinG. R. (1998). An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nat. Genet. 18, 136–141. 10.1038/ng0298-136
159
MinichielloL. (2009). TrkB signalling pathways in LTP and learning. Nat. Rev. Neurosci. 10, 850–860. 10.1038/nrn2738
160
MinichielloL.KorteM.WolferD.KuhnR.UnsickerK.CestariV.et al. (1999). Essential role for TrkB receptors in hippocampus-mediated learning. Neuron24, 401–414.
161
MiraouiH.DwyerA. A.SykiotisG. P.PlummerL.ChungW.FengB.et al. (2013). Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am. J. Hum. Genet. 92, 725–743. 10.1016/j.ajhg.2013.04.008
162
MolinaD. P.AriwodolaO. J.WeinerJ. L.Brunso-BechtoldJ. K.AdamsM. M. (2013). Growth hormone and insulin-like growth factor-I alter hippocampal excitatory synaptic transmission in young and old rats. Age (Dordr.)35, 1575–1587. 10.1007/s11357-012-9460-4
163
MoriceE.FarleyS.PoirierR.DalleracG.ChagneauC.PannetierS.et al. (2013). Defective synaptic transmission and structure in the dentate gyrus and selective fear memory impairment in the Rsk2 mutant mouse model of Coffin-Lowry syndrome. Neurobiol. Dis. 58, 156–168. 10.1016/j.nbd.2013.05.016
164
MuenkeM.GrippK. W.McDonald-McGinnD. M.GaudenzK.WhitakerL. A.BartlettS. P.et al. (1997). A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am. J. Hum. Genet. 60, 555–564.
165
Muinos-GimenoM.GuidiM.KagerbauerB.Martin-SantosR.NavinesR.AlonsoP.et al. (2009). Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders. Hum. Mutat. 30, 1062–1071. 10.1002/humu.21005
166
MutohT.TachiM.YanoS.MiharaT.YamamotoH. (2005). Impairment of Trk-neurotrophin receptor by the serum of a patient with subacute sensory neuropathy. Arch. Neurol. 62, 1612–1615. 10.1001/archneur.62.10.1612
167
NealeB. M.KouY.LiuL.Ma'ayanA.SamochaK. E.SaboA.et al. (2012). Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature485, 242–245. 10.1038/nature11011
168
Neves-PereiraM.CheungJ. K.PasdarA.ZhangF.BreenG.YatesP.et al. (2005). BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol. Psychiatry10, 208–212. 10.1038/sj.mp.4001575
169
Neves-PereiraM.MundoE.MugliaP.KingN.MacciardiF.KennedyJ. L. (2002). The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am. J. Hum. Genet. 71, 651–655. 10.1086/342288
170
NguyenA.RauchT. A.PfeiferG. P.HuV. W. (2010). Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain. FASEB J. 24, 3036–3051. 10.1096/fj.10-154484
171
NiehrsC. (2012). The complex world of WNT receptor signalling. Nat. Rev. Mol. Cell Biol. 13, 767–779. 10.1038/nrm3470
172
NikoletopoulouV.LickertH.FradeJ. M.RencurelC.GiallonardoP.ZhangL.et al. (2010). Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not. Nature467, 59–63. 10.1038/nature09336
173
NishimuneH.SanesJ. R.CarlsonS. S. (2004). A synaptic laminin-calcium channel interaction organizes active zones in motor nerve terminals. Nature432, 580–587. 10.1038/nature03112
174
NishiyamaM.SkoultchiA. I.NakayamaK. I. (2012). Histone H1 recruitment by CHD8 is essential for suppression of the Wnt-beta-catenin signaling pathway. Mol. Cell. Biol. 32, 501–512. 10.1128/MCB.06409-11
175
NordstromU.MaierE.JessellT. M.EdlundT. (2006). An early role for WNT signaling in specifying neural patterns of Cdx and Hox gene expression and motor neuron subtype identity. PLoS Biol. 4:e252. 10.1371/journal.pbio.0040252
176
NovakG.SeemanP.TallericoT. (2000). Schizophrenia: elevated mRNA for calcium-calmodulin-dependent protein kinase IIbeta in frontal cortex. Brain Res. Mol. Brain Res. 82, 95–100. 10.1016/S0169-328X(00)00188-1
177
NunezA.CarroE.Torres-AlemanI. (2003). Insulin-like growth factor I modifies electrophysiological properties of rat brain stem neurons. J. Neurophysiol. 89, 3008–3017. 10.1152/jn.00089.2003
178
O'BrienW. T.HarperA. D.JoveF.WoodgettJ. R.MarettoS.PiccoloS.et al. (2004). Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J. Neurosci. 24, 6791–6798. 10.1523/JNEUROSCI.4753-03.2004
179
OkerlundN. D.CheyetteB. N. (2011). Synaptic Wnt signaling-a contributor to major psychiatric disorders?J. Neurodev. Disord. 3, 162–174. 10.1007/s11689-011-9083-6
180
O'KuskyJ.YeP. (2012). Neurodevelopmental effects of insulin-like growth factor signaling. Front. Neuroendocrinol. 33, 230–251. 10.1016/j.yfrne.2012.06.002
181
OreficeL. L.WaterhouseE. G.PartridgeJ. G.LalchandaniR. R.ViciniS.XuB. (2013). Distinct roles for somatically and dendritically synthesized brain-derived neurotrophic factor in morphogenesis of dendritic spines. J. Neurosci. 33, 11618–11632. 10.1523/JNEUROSCI.0012-13.2013
182
O'RoakB. J.VivesL.FuW.EgertsonJ. D.StanawayI. B.PhelpsI. G.et al. (2012a). Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science338, 1619–1622. 10.1126/science.1227764
183
O'RoakB. J.VivesL.GirirajanS.KarakocE.KrummN.CoeB. P.et al. (2012b). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature485, 246–250. 10.1038/nature10989
184
OrtegaS.IttmannM.TsangS. H.EhrlichM.BasilicoC. (1998). Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc. Natl. Acad. Sci. U.S.A. 95, 5672–5677.
185
ParatchaG.LeddaF. (2008). GDNF and GFRalpha: a versatile molecular complex for developing neurons. Trends Neurosci. 31, 384–391. 10.1016/j.tins.2008.05.003
186
ParkM.ShenK. (2012). WNTs in synapse formation and neuronal circuitry. EMBO J. 31, 2697–2704. 10.1038/emboj.2012.145
187
PatzkeH.ErnsbergerU. (2000). Expression of neurexin Ialpha splice variants in sympathetic neurons: selective changes during differentiation and in response to neurotrophins. Mol. Cell. Neurosci. 15, 561–572. 10.1006/mcne.2000.0853
188
PerezJ. A.ClintonS. M.TurnerC. A.WatsonS. J.AkilH. (2009). A new role for FGF2 as an endogenous inhibitor of anxiety. J. Neurosci. 29, 6379–6387. 10.1523/JNEUROSCI.4829-08.2009
189
PerronJ. C.BixbyJ. L. (1999). Distinct neurite outgrowth signaling pathways converge on ERK activation. Mol. Cell. Neurosci. 13, 362–378. 10.1006/mcne.1999.0753
190
PetrikD.LagaceD. C.EischA. J. (2012). The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building?Neuropharmacology62, 21–34. 10.1016/j.neuropharm.2011.09.003
191
PoduriA.ChopraS. S.NeilanE. G.ElhosaryP. C.KurianM. A.MeyerE.et al. (2012a). Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy. Epilepsia53, e146–e150. 10.1111/j.1528-1167.2012.03538.x
192
PoduriA.EvronyG. D.CaiX.ElhosaryP. C.BeroukhimR.LehtinenM. K.et al. (2012b). Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron74, 41–48. 10.1016/j.neuron.2012.03.010
193
PollittA. Y.InsallR. H. (2009). WASP and SCAR/WAVE proteins: the drivers of actin assembly. J. Cell Sci. 122, 2575–2578. 10.1242/jcs.023879
194
PoonV. Y.ChoiS.ParkM. (2013). Growth factors in synaptic function. Front. Synaptic Neurosci. 5:6. 10.3389/fnsyn.2013.00006
195
PrioloM.LeroneM.BafficoM.BaldiM.RavazzoloR.CamaA.et al. (2000). Pfeiffer syndrome type 2 associated with a single amino acid deletion in the FGFR2 gene. Clin. Genet. 58, 81–83. 10.1034/j.1399-0004.2000.580116.x
196
PyottS. M.TranT. T.LeistritzD. F.PepinM. G.MendelsohnN. J.TemmeR. T.et al. (2013). WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta. Am. J. Hum. Genet. 92, 590–597. 10.1016/j.ajhg.2013.02.009
197
QiX. R.ZhaoJ.LiuJ.FangH.SwaabD. F.ZhouJ. N. (2013). Abnormal Retinoid and TrkB Signaling in the Prefrontal Cortex in Mood Disorders. Cereb. Cortex. [Epub ahead of print]. 10.1093/cercor/bht203
198
QuevedoC.AlcazarA.SalinasM. (2000). Two different signal transduction pathways are implicated in the regulation of initiation factor 2B activity in insulin-like growth factor-1-stimulated neuronal cells. J. Biol. Chem. 275, 19192–19197. 10.1074/jbc.M000238200
199
RaileK.KlammtJ.SchneiderA.KellerA.LaueS.SmithR.et al. (2006). Clinical and functional characteristics of the human Arg59Ter insulin-like growth factor i receptor (IGF1R) mutation: implications for a gene dosage effect of the human IGF1R. J. Clin. Endocrinol. Metab. 91, 2264–2271. 10.1210/jc.2005-2146
200
RamseyM. M.AdamsM. M.AriwodolaO. J.SonntagW. E.WeinerJ. L. (2005). Functional characterization of des-IGF-1 action at excitatory synapses in the CA1 region of rat hippocampus. J. Neurophysiol. 94, 247–254. 10.1152/jn.00768.2004
201
RayP.DevauxY.StolzD. B.YarlagaddaM.WatkinsS. C.LuY.et al. (2003). Inducible expression of keratinocyte growth factor (KGF) in mice inhibits lung epithelial cell death induced by hyperoxia. Proc. Natl. Acad. Sci. U.S.A. 100, 6098–6103. 10.1073/pnas.1031851100
202
ReardonW.WilkesD.RutlandP.PulleynL. J.MalcolmS.DeanJ. C.et al. (1997). Craniosynostosis associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis. J. Med. Genet. 34, 632–636.
203
ReichardtL. F. (2006). Neurotrophin-regulated signalling pathways. Philos. Trans. R. Soc. Lond. B Biol. Sci. 361, 1545–1564. 10.1098/rstb.2006.1894
204
RibasesM.GratacosM.ArmengolL.De CidR.BadiaA.JimenezL.et al. (2003). Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type. Mol. Psychiatry8, 745–751. 10.1038/sj.mp.4001281
205
RibasesM.GratacosM.Fernandez-ArandaF.BellodiL.BoniC.AnderluhM.et al. (2004). Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum. Mol. Genet. 13, 1205–1212. 10.1093/hmg/ddh137
206
RoschH.SchweigreiterR.BonhoefferT.BardeY. A.KorteM. (2005). The neurotrophin receptor p75NTR modulates long-term depression and regulates the expression of AMPA receptor subunits in the hippocampus. Proc. Natl. Acad. Sci. U.S.A. 102, 7362–7367. 10.1073/pnas.0502460102
207
RossoS. B.InestrosaN. C. (2013). WNT signaling in neuronal maturation and synaptogenesis. Front. Cell. Neurosci. 7:103. 10.3389/fncel.2013.00103
208
RossoS. B.SussmanD.Wynshaw-BorisA.SalinasP. C. (2005). Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nat. Neurosci. 8, 34–42. 10.1038/nn1374
209
RussoE.CitraroR.ConstantiA.De SarroG. (2012). The mTOR signaling pathway in the brain: focus on epilepsy and epileptogenesis. Mol. Neurobiol. 46, 662–681. 10.1007/s12035-012-8314-5
210
SanchezM. M.AlagbeO.FelgerJ. C.ZhangJ.GraffA. E.GrandA. P.et al. (2007). Activated p38 MAPK is associated with decreased CSF 5-HIAA and increased maternal rejection during infancy in rhesus monkeys. Mol. Psychiatry12, 895–897. 10.1038/sj.mp.4002025
211
SanhuezaM.McIntyreC. C.LismanJ. E. (2007). Reversal of synaptic memory by Ca2+/calmodulin-dependent protein kinase II inhibitor. J. Neurosci. 27, 5190–5199. 10.1523/JNEUROSCI.5049-06.2007
212
SarachanaT.HuV. W. (2013). Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder. Mol. Autism4, 14. 10.1186/2040-2392-4-14
213
Scearce-LevieK.RobersonE. D.GersteinH.CholfinJ. A.MandiyanV. S.ShahN. M.et al. (2008). Abnormal social behaviors in mice lacking Fgf17. Genes Brain Behav. 7, 344–354. 10.1111/j.1601-183X.2007.00357.x
214
SchmeisserM. J.BaumannB.JohannsenS.VindedalG. F.JensenV.HvalbyO. C.et al. (2012). IkappaB kinase/nuclear factor kappaB-dependent insulin-like growth factor 2 (Igf2) expression regulates synapse formation and spine maturation via Igf2 receptor signaling. J. Neurosci. 32, 5688–5703. 10.1523/JNEUROSCI.0111-12.2012
215
SchmittA. M.ShiJ.WolfA. M.LuC. C.KingL. A.ZouY. (2006). Wnt-Ryk signalling mediates medial-lateral retinotectal topographic mapping. Nature439, 31–37. 10.1038/nature04334
216
SchulzJ.SundinJ.LeaskS.DoneD. J. (2014). Risk of adult schizophrenia and its relationship to childhood IQ in the 1958 British birth cohort. Schizophr. Bull. 40, 143–151. 10.1093/schbul/sbs157
217
SchumacherJ.JamraR. A.BeckerT.OhlraunS.KloppN.BinderE. B.et al. (2005). Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol. Psychiatry58, 307–314. 10.1016/j.biopsych.2005.04.006
218
SenS.DumanR.SanacoraG. (2008). Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol. Psychiatry64, 527–532. 10.1016/j.biopsych.2008.05.005
219
SensiA.CerutiS.TrevisiP.GualandiF.BusiM.DonatiI.et al. (2011). LAMM syndrome with middle ear dysplasia associated with compound heterozygosity for FGF3 mutations. Am. J. Med. Genet. A155A, 1096–1101. 10.1002/ajmg.a.33962
220
ShinD. M.KoradaS.RaballoR.ShashikantC. S.SimeoneA.TaylorJ. R.et al. (2004). Loss of glutamatergic pyramidal neurons in frontal and temporal cortex resulting from attenuation of FGFR1 signaling is associated with spontaneous hyperactivity in mice. J. Neurosci. 24, 2247–2258. 10.1523/JNEUROSCI.5285-03.2004
221
ShotelersukV.IttiwutC.SrivuthanaS.MahatumaratC.LerdlumS.WacharasindhuS. (2002). Distinct craniofacial-skeletal-dermatological dysplasia in a patient with W290C mutation in FGFR2. Am. J. Med. Genet. 113, 4–8. 10.1002/ajmg.10449
222
SmeyneR. J.KleinR.SchnappA.LongL. K.BryantS.LewinA.et al. (1994). Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature368, 246–249. 10.1038/368246a0
223
SmollerJ. W.FinnC. T. (2003). Family, twin, and adoption studies of bipolar disorder. Am. J. Med. Genet. C Semin. Med. Genet. 123C, 48–58. 10.1002/ajmg.c.20013
224
SquarzoniP.ParveenF.ZanettiL.RistoratoreF.SpagnuoloA. (2011). FGF/MAPK/Ets signaling renders pigment cell precursors competent to respond to Wnt signal by directly controlling Ci-Tcf transcription. Development138, 1421–1432. 10.1242/dev.057323
225
SquassinaA.CostaM.CongiuD.ManchiaM.AngiusA.DeianaV.et al. (2013). Insulin-like growth factor 1 (IGF-1) expression is up-regulated in lymphoblastoid cell lines of lithium responsive bipolar disorder patients. Pharmacol. Res. 73, 1–7. 10.1016/j.phrs.2013.04.004
226
StevensH. E.SmithK. M.MaragnoliM. E.FagelD.BorokE.ShanabroughM.et al. (2010). Fgfr2 is required for the development of the medial prefrontal cortex and its connections with limbic circuits. J. Neurosci. 30, 5590–5602. 10.1523/JNEUROSCI.5837-09.2010
227
StockmeierC. A.MahajanG. J.KonickL. C.OverholserJ. C.JurjusG. J.MeltzerH. Y.et al. (2004). Cellular changes in the postmortem hippocampus in major depression. Biol. Psychiatry56, 640–650. 10.1016/j.biopsych.2004.08.022
228
StockmeierC. A.RajkowskaG. (2004). Cellular abnormalities in depression: evidence from postmortem brain tissue. Dialogues Clin. Neurosci. 6, 185–197.
229
StroppoloA.GuineaB.TianC.SommerJ.EhrlichM. E. (2001). Role of phosphatidylinositide 3-kinase in brain-derived neurotrophic factor-induced DARPP-32 expression in medium size spiny neurons in vitro. J. Neurochem. 79, 1027–1032. 10.1046/j.1471-4159.2001.00651.x
230
SudhofT. C. (2008). Neuroligins and neurexins link synaptic function to cognitive disease. Nature455, 903–911. 10.1038/nature07456
231
SullivanP. F.MagnussonC.ReichenbergA.BomanM.DalmanC.DavidsonM.et al. (2012). Family history of schizophrenia and bipolar disorder as risk factors for autism. Arch. Gen. Psychiatry69, 1099–1103. 10.1001/archgenpsychiatry.2012.730
232
TabatadzeN.TomasC.McGonigalR.LinB.SchookA.RouttenbergA. (2012). Wnt transmembrane signaling and long-term spatial memory. Hippocampus22, 1228–1241. 10.1002/hipo.20991
233
TalkowskiM. E.RosenfeldJ. A.BlumenthalI.PillalamarriV.ChiangC.HeilbutA.et al. (2012). Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell149, 525–537. 10.1016/j.cell.2012.03.028
234
TartagliaM.ValeriS.VelardiF.Di RoccoC.BattagliaP. A. (1997). Trp290Cys mutation in exon IIIa of the fibroblast growth factor receptor 2 (FGFR2) gene is associated with Pfeiffer syndrome. Hum. Genet. 99, 602–606.
235
TavorminaP. L.BellusG. A.WebsterM. K.BamshadM. J.FraleyA. E.McIntoshI.et al. (1999). A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am. J. Hum. Genet. 64, 722–731. 10.1086/302275
236
TekinM.HismiB. O.FitozS.OzdagH.CengizF. B.SirmaciA.et al. (2007). Homozygous mutations in fibroblast growth factor 3 are associated with a new form of syndromic deafness characterized by inner ear agenesis, microtia, and microdontia. Am. J. Hum. Genet. 80, 338–344. 10.1086/510920
237
TekinM.Ozturkmen AkayH.FitozS.BirnbaumS.CengizF. B.SennarogluL.et al. (2008). Homozygous FGF3 mutations result in congenital deafness with inner ear agenesis, microtia, and microdontia. Clin. Genet. 73, 554–565. 10.1111/j.1399-0004.2008.01004.x
238
TengH. K.TengK. K.LeeR.WrightS.TevarS.AlmeidaR. D.et al. (2005). ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J. Neurosci. 25, 5455–5463. 10.1523/JNEUROSCI.5123-04.2005
239
TerauchiA.Johnson-VenkateshE. M.TothA. B.JavedD.SuttonM. A.UmemoriH. (2010). Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature465, 783–787. 10.1038/nature09041
240
TerraccianoA.TanakaT.SutinA. R.SannaS.DeianaB.LaiS.et al. (2010). Genome-wide association scan of trait depression. Biol. Psychiatry68, 811–817. 10.1016/j.biopsych.2010.06.030
241
Terwisscha Van ScheltingaA. F.BakkerS. C.KahnR. S. (2010). Fibroblast growth factors in schizophrenia. Schizophr. Bull. 36, 1157–1166. 10.1093/schbul/sbp033
242
TesseurI.ZouK.EspositoL.BardF.BerberE.CanJ. V.et al. (2006). Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology. J. Clin. Invest. 116, 3060–3069. 10.1172/JCI27341
243
Thompson RayM.WeickertC. S.WyattE.WebsterM. J. (2011). Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders. J. Psychiatry Neurosci. 36, 195–203. 10.1503/jpn.100048
244
ToydemirR. M.BrassingtonA. E.Bayrak-ToydemirP.KrakowiakP. A.JordeL. B.WhitbyF. G.et al. (2006). A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am. J. Hum. Genet. 79, 935–941. 10.1086/508433
245
TrippA.OhH.GuillouxJ. P.MartinowichK.LewisD. A.SibilleE. (2012). Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder. Am. J. Psychiatry169, 1194–1202. 10.1176/appi.ajp.2012.12020248
246
TropeaD.GiacomettiE.WilsonN. R.BeardC.McCurryC.FuD. D.et al. (2009). Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc. Natl. Acad. Sci. U.S.A. 106, 2029–2034. 10.1073/pnas.0812394106
247
TropeaD.KreimanG.LyckmanA.MukherjeeS.YuH.HorngS.et al. (2006). Gene expression changes and molecular pathways mediating activity-dependent plasticity in visual cortex. Nat. Neurosci. 9, 660–668. 10.1038/nn1689
248
TurnerC. A.AkilH.WatsonS. J.EvansS. J. (2006). The fibroblast growth factor system and mood disorders. Biol. Psychiatry59, 1128–1135. 10.1016/j.biopsych.2006.02.026
249
TurnerC. A.LewisM. H.KingM. A. (2003). Environmental enrichment: effects on stereotyped behavior and dendritic morphology. Dev. Psychobiol. 43, 20–27. 10.1002/dev.10116
250
TurnerC. A.WatsonS. J.AkilH. (2012). The fibroblast growth factor family: neuromodulation of affective behavior. Neuron76, 160–174. 10.1016/j.neuron.2012.08.037
251
UddinL. Q.SupekarK.LynchC. J.KhouzamA.PhillipsJ.FeinsteinC.et al. (2013). Salience network-based classification and prediction of symptom severity in children with autism. JAMA Psychiatry70, 869–879. 10.1001/jamapsychiatry.2013.104
252
UmemoriH. (2009). Weaving the neuronal net with target-derived fibroblast growth factors. Dev. Growth Differ. 51, 263–270. 10.1111/j.1440-169X.2008.01079.x
253
UmemoriH.LinhoffM. W.OrnitzD. M.SanesJ. R. (2004). FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell118, 257–270. 10.1016/j.cell.2004.06.025
254
UtgeS. J.SoronenP.LoukolaA.KronholmE.OllilaH. M.PirkolaS.et al. (2010). Systematic analysis of circadian genes in a population-based sample reveals association of TIMELESS with depression and sleep disturbance. PLoS ONE5:e9259. 10.1371/journal.pone.0009259
255
UusitaloM.HeikkilaM.VainioS. (1999). Molecular genetic studies of Wnt signaling in the mouse. Exp. Cell Res. 253, 336–348. 10.1006/excr.1999.4710
256
Van AmerongenR.BernsA. (2006). Knockout mouse models to study Wnt signal transduction. Trends Genet. 22, 678–689. 10.1016/j.tig.2006.10.001
257
Van Der WaltJ. M.NoureddineM. A.KittappaR.HauserM. A.ScottW. K.McKayR.et al. (2004). Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease. Am. J. Hum. Genet. 74, 1121–1127. 10.1086/421052
258
Van KesterenR. E.GagatekJ. S.HagendorfA.GouwenbergY.SmitA. B.SyedN. I. (2008). Postsynaptic expression of an epidermal growth factor receptor regulates cholinergic synapse formation between identified molluscan neurons. Eur. J. Neurosci. 27, 2043–2056. 10.1111/j.1460-9568.2008.06189.x
259
Varela-NallarL.AlfaroI. E.SerranoF. G.ParodiJ.InestrosaN. C. (2010). Wingless-type family member 5A (Wnt-5a) stimulates synaptic differentiation and function of glutamatergic synapses. Proc. Natl. Acad. Sci. U.S.A. 107, 21164–21169. 10.1073/pnas.1010011107
260
VernesS. C.NewburyD. F.AbrahamsB. S.WinchesterL.NicodJ.GroszerM.et al. (2008). A functional genetic link between distinct developmental language disorders. N. Engl. J. Med. 359, 2337–2345. 10.1056/NEJMoa0802828
261
Vicario-AbejonC.CollinC.McKayR. D.SegalM. (1998). Neurotrophins induce formation of functional excitatory and inhibitory synapses between cultured hippocampal neurons. J. Neurosci. 18, 7256–7271.
262
VyssotskiA. L.Dell'omoG.PoletaevaI. IVyssotskD. L.MinichielloL.KleinR.et al. (2002). Long-term monitoring of hippocampus-dependent behavior in naturalistic settings: mutant mice lacking neurotrophin receptor TrkB in the forebrain show spatial learning but impaired behavioral flexibility. Hippocampus12, 27–38. 10.1002/hipo.10002
263
WangG.Van Der WaltJ. M.MayhewG.LiY. J.ZuchnerS.ScottW. K.et al. (2008). Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. Am. J. Hum. Genet. 82, 283–289. 10.1016/j.ajhg.2007.09.021
264
WassinkT. H.PivenJ.VielandV. J.HuangJ.SwiderskiR. E.PietilaJ.et al. (2001). Evidence supporting WNT2 as an autism susceptibility gene. Am. J. Med. Genet. 105, 406–413. 10.1002/ajmg.1401
265
WeiF.QiuC. S.LiauwJ.RobinsonD. A.HoN.ChatilaT.et al. (2002). Calcium calmodulin-dependent protein kinase IV is required for fear memory. Nat. Neurosci. 5, 573–579. 10.1038/nn855
266
WiderC.DachselJ. C.SotoA. I.HeckmanM. G.DiehlN. N.YueM.et al. (2009). FGF20 and Parkinson's disease: no evidence of association or pathogenicity via alpha-synuclein expression. Mov. Disord. 24, 455–459. 10.1002/mds.22442
267
WilliamsE. L.CasanovaM. F. (2011). Above genetics: lessons from cerebral development in autism. Transl. Neurosci. 2, 106–120. 10.2478/s13380-011-0016-3
268
WilliamsonW. R.HiesingerP. R. (2008). Synaptic patterning by morphogen signaling. Sci. Signal. 1:pe20. 10.1126/stke.118pe20
269
WongM. (2013). Mammalian target of rapamycin (mTOR) pathways in neurological diseases. Biomed. J. 36, 40–50. 10.4103/2319-4170.110365
270
WurdakH.IttnerL. M.LangK. S.LeveenP.SuterU.FischerJ. A.et al. (2005). Inactivation of TGFbeta signaling in neural crest stem cells leads to multiple defects reminiscent of DiGeorge syndrome. Genes Dev. 19, 530–535. 10.1101/gad.317405
271
Wyss-CorayT.BorrowP.BrookerM. J.MuckeL. (1997). Astroglial overproduction of TGF-beta 1 enhances inflammatory central nervous system disease in transgenic mice. J. Neuroimmunol. 77, 45–50.
272
Wyss-CorayT.LinC.YanF.YuG. Q.RohdeM.McConlogueL.et al. (2001). TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat. Med. 7, 612–618. 10.1038/87945
273
XieC. W.SayahD.ChenQ. S.WeiW. Z.SmithD.LiuX. (2000). Deficient long-term memory and long-lasting long-term potentiation in mice with a targeted deletion of neurotrophin-4 gene. Proc. Natl. Acad. Sci. U.S.A. 97, 8116–8121. 10.1073/pnas.140204597
274
XuB.GouldingE. H.ZangK.CepoiD.ConeR. D.JonesK. R.et al. (2003). Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat. Neurosci. 6, 736–742. 10.1038/nn1073
275
YamanakaY.KitanoA.TakaoK.PrasansuklabA.MushirodaT.YamazakiK.et al. (2011). Inactivation of fibroblast growth factor binding protein 3 causes anxiety-related behaviors. Mol. Cell. Neurosci. 46, 200–212. 10.1016/j.mcn.2010.09.003
276
Yilmazer-HankeD. M.Faber-ZuschratterH.BlumckeI.BickelM.BeckerA.MawrinC.et al. (2007). Axo-somatic inhibition of projection neurons in the lateral nucleus of amygdala in human temporal lobe epilepsy: an ultrastructural study. Exp. Brain Res. 177, 384–399. 10.1007/s00221-006-0680-7
277
YoshiiA.MurataY.KimJ.ZhangC.ShokatK. M.Constantine-PatonM. (2011). TrkB and protein kinase Mzeta regulate synaptic localization of PSD-95 in developing cortex. J. Neurosci. 31, 11894–11904. 10.1523/JNEUROSCI.2190-11.2011
278
YuH.WangD. D.WangY.LiuT.LeeF. S.ChenZ. Y. (2012). Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants. J. Neurosci. 32, 4092–4101. 10.1523/JNEUROSCI.5048-11.2012
279
YuH.WangY.PattwellS.JingD.LiuT.ZhangY.et al. (2009). Variant BDNF Val66Met polymorphism affects extinction of conditioned aversive memory. J. Neurosci. 29, 4056–4064. 10.1523/JNEUROSCI.5539-08.2009
280
ZeevB. B.BebbingtonA.HoG.LeonardH.De KlerkN.GakE.et al. (2009). The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome. Neurology72, 1242–1247. 10.1212/01.wnl.0000345664.72220.6a
281
ZhaX. M.BishopJ. F.HansenM. R.VictoriaL.AbbasP. J.MouradianM. M.et al. (2001). BDNF synthesis in spiral ganglion neurons is constitutive and CREB-dependent. Hear. Res. 156, 53–68. 10.1016/S0378-5955(01)00267-2
282
ZhangX.ZhuJ.YangG. Y.WangQ. J.QianL.ChenY. M.et al. (2007). Dishevelled promotes axon differentiation by regulating atypical protein kinase C. Nat. Cell Biol. 9, 743–754. 10.1038/ncb1603
283
ZintzarasE. (2007). Brain-derived neurotrophic factor gene polymorphisms and schizophrenia: a meta-analysis. Psychiatr. Genet. 17, 69–75. 10.1097/YPG.0b013e32801119da
284
ZornerB.WolferD. P.BrandisD.KretzO.ZacherC.MadaniR.et al. (2003). Forebrain-specific trkB-receptor knockout mice: behaviorally more hyperactive than “depressive.”Biol. Psychiatry54, 972–982. 10.1016/S0006-3223(03)00418-9
285
ZukoA.KleijerK. T.Oguro-AndoA.KasM. J.Van DaalenE.Van Der ZwaagB.et al. (2013). Contactins in the neurobiology of autism. Eur. J. Pharmacol. 719, 63–74. 10.1016/j.ejphar.2013.07.016
Summary
Keywords
synapse, synaptogenesis, growth factor, psychiatry, mental illness
Citation
Williams AJ and Umemori H (2014) The best-laid plans go oft awry: synaptogenic growth factor signaling in neuropsychiatric disease. Front. Synaptic Neurosci. 6:4. doi: 10.3389/fnsyn.2014.00004
Received
16 December 2013
Accepted
21 February 2014
Published
18 March 2014
Volume
6 - 2014
Edited by
Akira Yoshii, University of Illinois at Chicago, USA
Reviewed by
Ka Wan Li, VU University, Netherlands; Ki Ann Goosens, Massachusetts Institute of Technology, USA
Copyright
© 2014 Williams and Umemori.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hisashi Umemori, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Center for Life Sciences 13074, Boston, MA 02115, USA e-mail: hisashi.umemori@childrens.harvard.edu
This article was submitted to the journal Frontiers in Synaptic Neuroscience.
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.