Synapses are complex structures that allow communication between neurons in the central nervous system. Studies conducted in vertebrate and invertebrate models have contributed to the knowledge of the function of synaptic proteins. The functional synapse requires numerous protein complexes with specialized functions that are regulated in space and time to allow synaptic plasticity. However, their interplay during neuronal development, learning, and memory is poorly understood. Accumulating evidence links synapse proteins to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. In this review, we describe the way in which several proteins that participate in cell adhesion, scaffolding, exocytosis, and neurotransmitter reception from presynaptic and postsynaptic compartments, mainly from excitatory synapses, have been associated with several synaptopathies, and we relate their functions to the disease phenotype.
Communication among neurons in the central nervous system (CNS) is mediated by specialized contacts named synapses that are formed by presynaptic and postsynaptic compartments. The presynapse contains the active zone (AZ), a region that concentrates proteins involved in the recruitment and fusion of synaptic vesicles (SVs), which release neurotransmitter into the synaptic cleft [
Molecular composition of a central chemical synapse. The image shows a typical excitatory synapse in the CNS. Pre- and postsynaptic proteins are organized in macromolecular functional complexes playing different roles in scaffolding, exocytosis, endocytosis, and signaling in their respective compartments. In addition, the most relevant adhesion molecules are represented.
In the previous three decades, the molecular composition and the organization of the pre- and postsynaptic compartments have been greatly elucidated by a combination of biochemistry, proteomic, genetic, superresolution microscopy, and 3D electron microscopy techniques [
Human genetic studies and animal models of neurological diseases have led to an emerging concept in neurobiology; the term is “synaptopathy,” which refers to brain disorders that have arisen from synaptic dysfunction, including neurodevelopmental (autism spectrum disorders (ASD), intellectual disability (ID), Fragile X syndrome (FXS), Down Syndrome, attention deficit hyperactivity disorder (ADHD), and epilepsy) and neuropsychiatric disorders (bipolar disorder (BPD), schizophrenia (SCZ), and major depressive disorder (MDD)) and neurodegenerative diseases (Alzheimer’s disease (AD), Huntington’s Disease (HD), and Parkinson’s Disease) (Figure
Schematic representation of neurological disorders associated with synaptic protein dysfunction. The image summarizes the neurological diseases described in this review represented by color code: neurodevelopmental (green spectrum), neuropsychiatric (blue spectrum), and neurodegenerative (red spectrum). The number of synaptic proteins involved in each category is proportionally illustrated. AD, Alzheimer’s disease; ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; BPD, bipolar spectrum disorder; FXS, Fragile X syndrome; HD, Huntington’s Disease; ID, intellectual disability; MDD, major depressive disorder; SCZ, schizophrenia.
Among the neurodevelopmental disorders, ASD and FXS are synaptopathy-related diseases that are mostly determined by genetic factors. On the one hand, ASD is heritable in 80% of cases, and impaired individuals manifest a variety of intellectual deficiencies from social communication deficits to repetitive and abnormal behaviors [
Here, we describe pre- and postsynaptic proteins that are involved in the pathology of neurological disease originating at chemical synapses in the CNS and are known to support synaptic function via different mechanisms, including adhesion, scaffolding, SV cycling, and signaling.
Presynaptic sites are characterized using electron microscopy by an electrodense material that represents the AZ where specific proteins aggregate to regulate the cycle of SVs. The AZ translates an action potential into a chemical signal that induces the release of neurotransmitters into the synaptic cleft. Synaptic vesicles undergo cycles of exocytosis and endocytosis regulated by AZ proteins. AZ proteins participate in the active modulation of exocytosis according to the circuit requirements. In fact, once synapses are established, AZ undergoes molecular remodeling during their lifespan to support the requirements of synaptic activity and plasticity. Therefore, AZ proteins have to interact coordinately to accomplish normal and dynamic synaptic functions. Altogether, AZ proteins, the cytoskeleton, and adhesion and signaling molecules maintain the integrity of the presynapse.
A group of proteins that are directly involved in the exocytosis of SVs is the SNARE (SNAP Soluble NSF Attachment Protein REceptor) complex formed by synaptobrevin, syntaxin, and synaptosomal-associated protein 25 (SNAP25), which mediates SV fusion with the AZ plasma membrane [
Presynaptic proteins involved in different synaptopathies and their role in physiological synaptic function.
Function | Neurological disease | References | |
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Synapsin 1 | Mobilization, release, and tethering of SV to the cytoskeleton away from the AZ | BPD | [ |
Epilepsy | [ | ||
ASD | [ | ||
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Synapsin 2 | SVs mobilization and regulation of the number and density of the reserve pool | SCZ | [ |
Epilepsy | [ | ||
BPD | [ | ||
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Synapsin 3 | Synaptogenesis and modulation of neurotransmitter release | SCZ | [ |
BPD | [ | ||
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Synaptophysin | Control of SVs endocytosis | SCZ | [ |
BPD | [ | ||
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RIMs | Docking, SV fusion, and neurotransmitter release | SCZ | [ |
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Piccolo | AZ scaffolding protein | SCZ | [ |
MDD | [ | ||
BPD | [ | ||
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SNAP25 | Mediation of vesicle docking and fusion | BPD | [ |
SCZ | [ | ||
ADHD | [ | ||
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SynCAM1 | Synapse formation, synaptic plasticity, and axonal pathfinding | ASD | [ |
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Cadherin | Selection of neuronal target, synapse formation, and plasticity | SCZ | [ |
BPD | [ | ||
ASD | [ | ||
ADHD | [ | ||
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NRXN1 | Formation and maturation of the synapse | ASD | [ |
SCZ | [ |
The table summarizes the physiological synaptic function of presynaptic proteins whose alterations result in synaptopathies related to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; AZ, active zone; BPD, bipolar disorder; MDD, major depressive disorder; NRXN, neurexin; RIM, Rab3a interacting molecule; SCZ, schizophrenia; SynCAMs, Synaptic adhesion molecules; SV, synaptic vesicle.
Schematic representation of synaptic proteins associated with synaptopathies. (a) Presynaptic and (b) postsynaptic proteins involved in human synaptopathies described in this review are color highlighted. Mutations in a gene or gene combination for a synaptic protein may lead to neurodevelopment, neuropsychiatric, and neurodegenerative diseases.
Synapsins are phosphoproteins that are associated with the membrane of SVs and play a role in tethering SVs to the cytoskeleton away from the AZ. The phosphorylation of synapsin during an action potential induces the release of SVs from the reserve pool, allowing their movement toward the presynaptic AZ to release neurotransmitter. Therefore, synapsin will regulate the number of vesicles accessible for exocytosis. In vertebrates, three synapsin genes have been described (
Synaptophysin is a SV glycoprotein and the most widely used synaptic marker. Interestingly, KO mice for synaptophysin are normal, but electrophysiological experiments indicate that this protein is necessary for efficient endocytosis of SV in hippocampal neurons [
RIMs were first identified as Rab3-interacting molecules [
Although an association with human SCZ has not been attributed to RIM1
Piccolo is a multidomain CAZ protein and the largest protein in the presynapse. Piccolo is a nontransmembrane protein that is transported during development into newly forming synapses in a dense core vesicle of Golgi origin [
In population studies, Piccolo has demonstrated an association with some psychiatric disorders. Weidenhofer et al. reported an increase in the gene expression of
SNAP25 is a t-SNARE protein and a key component of the SNARE protein complex, the machinery involved in the fusion of SVs. SNAP25 assembles with syntaxin and synaptobrevin to mediate vesicle docking and Ca2+-triggered fusion.
SNAP25 has been involved in several human neuropsychiatric disorders. Abnormal levels of the protein have been found in the postmortem brain of bipolar patients [
The role of SNAP25 in neuropsychiatry disorders might not only be explained by its novel function in exocytosis because recent articles have assigned postsynaptic functions to this SNARE protein. Accordingly, SNPA25 was assigned a role in NMDAR and kainate-type receptor trafficking [
Synaptic adhesion molecules (SynCAMs) are molecules that actively participate in synapse formation and plasticity [
Cadherin is a Ca2+-dependent homophilic cell adhesion molecule with a role in neuronal target selection, synapse formation, and plasticity in the vertebrate CNS. It comprises a superfamily of approximately 100 members expressed in brain. In the CNS, cadherin expression follows a spatiotemporal pattern, suggesting an important role in specific circuit development [
Several neuropsychiatric diseases have been associated with cadherins, such as SCZ, ASD, BPD, and alcoholism [
NRXNs are presynaptic adhesion molecules that interact transsynaptically with postsynaptic neuroligins (NLs), an interaction that is known to be important for synaptogenesis and synapse maintenance [
Studies conducted
The first report linking NRXN to a neurodevelopmental disorder was performed in a boy with ASD in whom the promoter and exons 1–5 were deleted from the
The PSD is a dynamic lattice-like array composed of interacting proteins lining the postsynaptic membrane that organize and stabilize synaptic receptors, ion channels, structural proteins, and signaling molecules required for normal synaptic transmission and synaptic function [
Postsynaptic proteins involved in different synaptopathies and their role in physiological synaptic function.
Protein | Function | Neurological disease | References |
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NL1 | Memory formation and maturation of excitatory synapses | ASD | [ |
AD | [ | ||
FXS | [ | ||
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NL2 | Formation and remodeling of inhibitory synapses | SCZ | [ |
ASD | [ | ||
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NL3 | Formation and remodeling of excitatory and inhibitory synapses | ASD | [ |
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NL4 | Formation and remodeling of excitatory and inhibitory synapses | ASD | [ |
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NMDARs | Regulation of synaptic plasticity and memory formation | ASD | [ |
SCZ | [ | ||
AD | [ | ||
HD | [ | ||
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KARs | Maturation of neural circuits during development | ASD | [ |
SCZ | [ | ||
BPD | [ | ||
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AMPARs | Mediators of excitatory transmission and synaptic plasticity | ASD | [ |
SCZ | [ | ||
BPD | [ | ||
MDD | [ | ||
FXS | [ | ||
HD | [ | ||
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mGluRs | Regulation of neuronal excitability, learning, and memory | ASD | [ |
ID | [ | ||
FXS | [ | ||
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PSD-95 | Stabilization of the synapse, and regulation of synaptic strength, transmission, and plasticity | AD | [ |
ASD | [ | ||
SCZ | [ | ||
HD | [ | ||
FXS | [ | ||
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Shank1 | Regulation of the structural and functional organization of the dendritic spines | ASD | [ |
SCZ | [ | ||
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Shank2 | Synaptogenesis; regulation of the molecular structure and modulation of interacting proteins in the PSD | ASD | [ |
ID | [ | ||
SCZ | [ | ||
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Shank3 | Synapse formation, dendritic spine maturation, and synaptic plasticity | ASD | [ |
PMS | [ | ||
SCZ | [ | ||
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Homer | Organization, stabilization and function of the PSD, and contribution in dendritic spine morphogenesis | SCZ | [ |
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SynGAP | Involvement in the cognitive development and synaptic transmission and function | SCZ | [ |
ASD | [ | ||
ID | [ | ||
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Gephyrin | Clustering and localization of glycine and GABA receptors at inhibitory synapses | ASD | [ |
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Epilepsy | [ | ||
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DISC1 | Regulation of synaptic plasticity | SCZ | [ |
Depression | [ | ||
BPD | [ | ||
ASD | [ | ||
AD | [ |
The table summarizes the physiological synaptic function of postsynaptic proteins whose alterations result in synaptopathies related to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. AD, Alzheimer’s disease; AMPARs,
NLs are postsynaptic cell adhesion proteins that participate in associations with presynaptic NRXNs in synaptogenesis through the recruitment to synaptic sites of receptors, channels, and signaling molecules. NLs constitute a multigene family of brain-specific membrane proteins composed of different isoforms in humans, including NL1, NL2, NL3, NL4, and NL4Y (occasionally referred to as NL5) [
NLs are well-accepted molecules that participate in the pathogenic mechanism of diverse neurological diseases and exert a strong genetic influence on developmental disorders. It has been reported that an aberrant form of NL at the postsynaptic membrane, an anomalous association with NRXN, or both anomalies trigger an abnormal excitatory and inhibitory balance and the underlying development of cognitive disorders.
A proper NL1 level, especially in the hippocampus, is crucial for memory formation. Moreover, impairment of the NL1 level might induce the development of autism-related symptoms [
In addition to its involvement in AD pathology, NL1 is known to participate in molecular mechanisms related to other neurological diseases [
Several studies have linked NL2 with symptoms related to neurological diseases, such as anxiety and SCZ, or alterations in normal behavior. In a genetic study of 584 SCZ patients, several mutations were found in the
For the
Several deletions of X-chromosomal DNA in the
Glutamate is considered the major excitatory neurotransmitter in the human brain, and the pathophysiology of several mental disorders is known to depend on glutamatergic system activity. Glutamate receptors comprise the ionotropic (iGluRs) and metabotropic glutamate receptors (mGluRs). iGluRs include NMDA, AMPA, and kainate receptors based on structural, pharmacological, and physiological properties.
NMDARs are formed by three subunits called GluN1-3 and different splice variants [
Several lines of evidence indicate that NMDARs are involved in different ASDs. De novo mutations in the GluN2B (
In AD patients, the glutamatergic system, especially NMDAR-mediated transmission, appears to be strongly affected because NMDARs are activated by the accumulation of A
Similarly, several HD transgenic mouse models have indicated that NMDARs, as well as the GluN2B subunit, are involved in the pathology of HD. The motor learning deficits manifested by YAC128 mice expressing the mutated Htt (mHtt) were attenuated by chronic extrasynaptic NMDAR blockade with memantine [
Kainate receptors (KARs), which are highly expressed in the cortex and hippocampus, are targeted to synapses, where they play specific roles in the maturation of neural circuits during development [
Some abnormalities in genes encoding the glutamate receptor subunits of the kainate type, such as
AMPARs are glutamate receptors that mediate fast synaptic transmission in the CNS. They are formed by the heterotetrameric combination of four subunits: GluR1-4, which determine the functional properties of AMPARs.
A deletion mutation in the
However, a role for AMPAR in the pathology of SCZ cannot be discarded because olanzapine, an atypical antipsychotic drug, has a therapeutic effect on memory dysfunction and cognitive impairment manifested in SCZ patients through the modulation of synaptic plasticity caused by the upregulation of GluR1 Ser845 phosphorylation [
Therefore, several lines of evidence indicate that the proper function of AMPARs, the major mediators of excitatory transmission in the CNS, is highly important for synaptic plasticity and cognitive functions, as evidenced by the association with several and different neurological disorders including ASDs, SCZ, AD, FXS, and HD [
mGluRs are involved in the regulation of neuronal excitability, learning, and memory and are classified in three groups as follows: mGluR1 and mGluR5 belong to the group 1 family; mGluR2, mGluR3, and mGluR4 form the group 2 family; and mGluR6, mGluR7, and mGluR8 are included in the group 3 family. These receptors are found synaptically and extrasynaptically. Group I members, which comprise mainly postsynaptic receptors that activate neuronal depolarization and excitability, are coupled to Gq/G11 and activated phospholipase Cb to generate inositol 1,4,5-triphosphate (IP3) and diacylglycerol with the consequent mobilization of calcium and activation of protein kinase C (PKC). In contrast, groups 2 and 3 members are mostly presynaptic receptors that are localized in positions where they inhibit synaptic vesicle release through Gi/o proteins.
Some evidence indicates that mGluRs are involved in both nonsyndromic [
The postsynaptic density protein 95 (PSD-95; also known as DLG4 and SAP90) is the most abundant protein in excitatory chemical synapses and the main scaffolding protein at the PSD. In fact, PSD-95 contributes to synaptic stabilization, strength, and transmission, and its proper regulation is known to be essential for accurate synaptic development and plasticity. PSD-95 belongs to the membrane-associated guanylate kinase (MAGUK) protein family. All of these proteins possess three independent PDZ (PSD-95, Dlg1, and zonula occludens-1 proteins (zo-1)) domains through which they interact with glutamate receptors, cell adhesion molecules, and cytoskeletal elements. The PDZ domain of PSD-95 binds to different postsynaptic proteins; for example, PDZ2 interacts with NR2 and NR1 of NMDARs [
Synaptic alterations in AD are often correlated with cognitive changes. Regarding the association between the alterations in PSD-95 and AD, it is known that during brain aging, A
The role of PSD-95 in the etiology of ASD is less clear because no rare genetic mutations in PSD-95 have been associated with ASDs to date; however,
Reduction of the hippocampal size is one of the characteristics of SCZ patients, and it has been reported that the CA1 region of the hippocampus plays an important role in the pathophysiology of SCZ. In postmortem brains of SCZ patients, the expression of PSD-95 is reduced together with its known interacting proteins Homer1 and mGluR1 [
It is known that PSD-95 possesses a binding site for FMRP, the FXS-related protein, and that its translation depends on the absence of this protein in FXS patients [
In summary, any alterations of the synaptic levels of PSD-95, a key molecule in PSD organization and function, may affect interactions with its partners and contribute to the development of several CNS diseases.
The members of the Shank/ProSAP family, Shank1, Shank2, and Shank3, are multidomain scaffold proteins located at the PSD of glutamatergic synapses that interact with a large variety of membrane and cytoplasmic proteins. Shank proteins are expressed in areas of the brain that are essential for cognition and learning and trigger a crucial role in spine formation and maturation [
Human genetic studies have strongly linked Shank genes, including
Several human genetic studies have indicated that Shank2 is involved in ASD and ID [
Loss of one copy of the
Shank3 is a well-known PSD protein in excitatory synapses and plays an important role in synaptic plasticity and functional coupling between presynaptic neurotransmitter release and a precise and rapid postsynaptic response. However, less is known about how defects in Shank3 could participate in the pathology of diseases such as ASD and SCZ. A recent study showed that Shank3 activation and localization in rat hippocampal neuron dendritic spines is regulated by zinc [
Homer is a family of scaffolding proteins formed by three members with a conserved aminoterminal enabled/vasodilator-stimulated phosphoproteins homolog 1 (EVH1) domain that binds to proline-rich sequences of mGluR [
SynGAP1, which is a postsynaptic component of the PSD, plays an important and essential role in the development of cognition and proper synaptic function. It has been reported that SynGAP interacts with PSD-95 [
Mice with a heterozygous null mutation of
Although in this review we preferentially considered the most important pre- and postsynaptic proteins involved in synaptopathies located at the AZ and PSD, respectively, of excitatory synapses, gephyrin (gphn) is also included because it is a key scaffolding protein at the postsynaptic membrane that plays an essential role through its interactions with NL2, a previously described protein, and collybistin in the clustering and localization of glycine and the
Interestingly, gphn is well-known to be involved in several neurological disorders including ASD, SCZ, and epilepsy because it is functionally linked to various synaptic proteins that represent a genetic risk for the development of neurological diseases such as NLs, NRXNs, and collybistin. In particular, exonic gene microdeletions in
DISC1, a protein encoded by the
Different mouse models have reported that DISC1 is involved in synapse function and related to neurological diseases such as depression [
In addition, it is noteworthy that, surprisingly, an increased amount of insoluble DISC1 oligomer aggregates was detected in the postmortem brain of SCZ patients, demonstrating a common link with other neurological disorders characterized by protein aggregation such as AD and HD [
A highlight characteristic of several AZ proteins, such as Piccolo and RIM, is their multidomain structure. Piccolo and RIM form homo and hetero-oligomers at the CAZ and exert their synaptic functions through molecular interactions with different binding targets. The functions and interactions of Piccolo include (a) actin cytoskeleton dynamic (profilin, Daam1, Abp1, and GIT1), (b) exocytosis (cAMP-GEFII), (c) endocytosis (PRA1 and GIT1), (d) protein turnover (Siah1), (e) membrane trafficking (Epc2), (f) calcium signaling (L-type Ca2+ channel), (g) scaffolding (Bassoon, RIM, Munc13, and ELKS), and (h) SV priming (RIM, Munc13) (Figure
Domain structure of two active zone proteins associated with synaptopathies. The diagrams show the multimodular organization of (a) Piccolo and (b) RIM, and their interaction with other proteins. Arrows indicate binding reactions. Domains are shown in colored boxes and designations are indicated by standard abbreviations.
Therefore, mutations on Piccolo and/or RIM genes rendering a mutated protein or altered levels of protein expression could produce functional imbalances at the synapse due to abnormal interactions with their respective partners. Consequently, neuronal circuits might be impaired responding suboptimally to environmental requirements affecting synaptic plasticity, which is known to be altered in many neurological diseases.
Genetic studies of human synaptopathies together with animal models have revealed that in most cases a disease cannot be explained by the gene mutation of a single synaptic protein, and, similarly, abnormal individual expression of different synaptic proteins can trigger the same or a similar disease phenotype. Accordingly, GWA studies that have identified specific genes associated with synaptopathies sometimes do not replicate all of the symptomatology of the disease in animal models, suggesting the participation of other genes. This phenomenon is not unexpected because synaptic proteins are coupled to a highly dynamic interactome that regulates basal and plastic synapse functions. Hence, additional GWA studies are necessary to identify most of the defective gene variants and the brain region harboring the molecular alteration in a specific synaptopathy. Such findings in humans may be used to create suitable animal models that closely mimic the human defect, allowing detailed studies of the physiological alterations. Therefore, this will allow the consideration of specific pharmacological therapies for the underlying synaptopathic genotype and phenotype.
Amyloid-
Actin binding protein
Alzheimer’s disease
Attention deficit hyperactivity disorder
Amyloid precursor protein
Autism spectrum disorders
Active zone
Bipolar disorder
Cytomatrix at the active zone
Central nervous system
Enabled/vasodilator-stimulated phosphoproteins homolog 1
Filamentous actin
Fragile X retardation protein
Fragile X syndrome
Gamma aminobutyric acid
gphn
Genome-wide association
Huntington’s Disease
Huntingtin
Intellectual disability
Ionotropic-glutamate receptors
Kainate receptors
Knock-out
Long-term potentiation
Major depressive disorder
Neuroligins
Metabotropic glutamate receptors
Neurexin
Positive and negative syndrome scale
Phelan-McDermid syndrome
Protein kinase C
Prenylated rab3A acceptor
Postsynaptic density
Rab3 interacting molecules
RIM-binding protein
Schizophrenia
Short hairpin RNA interference
Synaptosomal-associated protein 25
SNAP Soluble NSF Attachment Protein Receptor
Single nucleotide polymorphism
Synaptic adhesion molecules
Synaptic vesicles
Tropomyosin receptor kinase B
Transient receptor potential canonical-1
Voltage-dependent Ca2+ channels.
All authors declare no conflict of interests.
Viviana I. Torres and Daniela Vallejo contributed equally to this work.
This work was supported by grants from the Basal Center of Excellence in Aging and Regeneration (CONICYT-PFB 12/2007), and FONDECYT (no. 1160724) to N. C. Inestrosa. D. Vallejo had a CONICYT Postdoctoral Fellowship (no. 3170043), and V. Torres was a Research Associate of Center of Aging and Regeneration. The authors also thank the Sociedad Química y Minera de Chile (SQM) for a special grant on “The Effects of Lithium on Health and Disease.”