Postsynaptic density proteins and their involvement in neurodevelopmental disorders

Postsynaptic density proteins and their involvement in neurodevelopmental disorders Abstract Synaptic connections are essential for neural circuits in order to convey brain functions. The postsynaptic density (PSD) is a huge protein complex associated with postsynaptic membranes of excitatory synapses. In mammals, the PSD is composed of more than 1,000 proteins including receptors, scaffold proteins, signalling enzymes and cytoskeletal proteins. PSD proteins are crucial for synaptic transmission and plasticity. Proteomic studies have revealed the composition of PSD proteins in various species, brain regions and specific physiological conditions. Abnormalities with PSD proteins are linked to various neuropsychiatric diseases including neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Here, we review different kinds of proteomic studies of the PSD and the involvement of PSD proteins in physiological and pathological conditions. autism, proteomics, PSD (postsynaptic density), PSD-95, schizophrenia Neurons connect to each other to form neural networks via junctions called synapses. In the mammalian brain, most glutamatergic excitatory synapses are situated on tiny protrusions along dendrites, called dendritic spines (Fig. 1) (1, 2). The postsynaptic density (PSD) is an electron-dense structure beneath the postsynaptic membrane of excitatory synapses and is usually located at the tip of the dendritic spine (Fig. 1) (2–4). The PSD is composed of a densely packed protein complex that typically forms a disk-like structure with a diameter of 200–800 nm and a thickness of 30–60 nm in the mammalian brain (2–4). Proteomic studies have revealed that PSDs are composed of thousands of different proteins, including neurotransmitter receptors, cell adhesion molecules, scaffold proteins, signalling enzymes, cytoskeleton proteins and membrane trafficking proteins (2, 4). It is now known that mutations of many PSD proteins are associated with human neurological and psychiatric diseases, including autism spectrum disorder (ASD, hereafter) and schizophrenia (5). Recent large-scale genomic studies have extended the knowledge about the genetic architecture of psychiatric disorders and showed an excess of disruptive mutations in ASD and schizophrenia in several postsynaptic gene sets (6). Whereas there are comprehensive review articles regarding this topic (7–10), in this review, we summarize previous studies of PSD proteome and the involvement of PSD proteins in psychiatric diseases. Fig. 1 View largeDownload slide Dendritic spines and PSD. Mouse hippocampal neurons transfected with PSD-95-GFP (green) and dsRed (red). Dendritic spines are small protrusions along dendrites. PSD-95 (PSD marker) is localized mainly to the spine tip. Fig. 1 View largeDownload slide Dendritic spines and PSD. Mouse hippocampal neurons transfected with PSD-95-GFP (green) and dsRed (red). Dendritic spines are small protrusions along dendrites. PSD-95 (PSD marker) is localized mainly to the spine tip. Core components in PSDs PSDs can be purified from brain samples by differential centrifugation and sucrose density gradient centrifugation, followed by detergent extraction by Triton X-100, which does not solubilize PSDs (11). This method is widely used for proteomic analysis of the PSD. Studies in the early 2000s identified most of the major PSD components through mass spectrometry-based analysis of purified PSD fractions (12–16). More recently, the dataset of the mammalian PSD proteome has been updated (17, 18) and summarized on the Genes to Cognition website (http://www.genes2cognition.org/), together with other proteome datasets published by this group. In mouse and human brains, 1,556 and 1,461 proteins were identified as PSD proteins, respectively, and 1,019 proteins were identified in both species (17, 18) (Fig. 2A and B). Among them, 984 proteins in mouse and 748 proteins in human (547 in both) were identified in triplicate and defined as ‘consensus’ PSD proteins (17, 18) (Fig. 2A and B). Fig. 2 View largeDownload slide Major PSD proteins. (A) Well-known proteins in the PSD. The exterior side is enriched in glutamate receptors (NMDAR and AMPAR) and adhesion molecules (N-Cadherin, NLGN, LRRTM and EphR). NMDAR and AMPAR are associated with a matrix of scaffold proteins including PSD-95, GKAP, SHANK and Homer. PSD-95 also interacts with NLGN and small GTPase regulators SYNGAP and Kalirin-7. SHANK is associated with F-actin through Cortactin. Homer interacts with mGluR. CaMKII kinase is associated with F-actin and NMDAR. Arc interacts with CaMKII. FMRP-CYFIP1 complex represses translation of target mRNA. (B) Overlap of protein composition between each protein complex and indicated subsets of proteins in the PSD. PSD: consensus PSD proteins and total PSD proteins identified both in human and mouse brain are shown (17, 18), NMDAR complex: GluN2B peptide interacting proteins identified both in human (biopsy) and mouse brain are shown (16, 40), PSD-95 complex: PSD-95 interacting proteins identified in two independent experiments are shown (42, 43), Arc complex: proteins reported previously in (32), AMPAR complex: proteins reported previously in (41), mGluR5 complex: proteins reported previously in (45). The overlap of the proteins was analysed using VennDIS (75). Fig. 2 View largeDownload slide Major PSD proteins. (A) Well-known proteins in the PSD. The exterior side is enriched in glutamate receptors (NMDAR and AMPAR) and adhesion molecules (N-Cadherin, NLGN, LRRTM and EphR). NMDAR and AMPAR are associated with a matrix of scaffold proteins including PSD-95, GKAP, SHANK and Homer. PSD-95 also interacts with NLGN and small GTPase regulators SYNGAP and Kalirin-7. SHANK is associated with F-actin through Cortactin. Homer interacts with mGluR. CaMKII kinase is associated with F-actin and NMDAR. Arc interacts with CaMKII. FMRP-CYFIP1 complex represses translation of target mRNA. (B) Overlap of protein composition between each protein complex and indicated subsets of proteins in the PSD. PSD: consensus PSD proteins and total PSD proteins identified both in human and mouse brain are shown (17, 18), NMDAR complex: GluN2B peptide interacting proteins identified both in human (biopsy) and mouse brain are shown (16, 40), PSD-95 complex: PSD-95 interacting proteins identified in two independent experiments are shown (42, 43), Arc complex: proteins reported previously in (32), AMPAR complex: proteins reported previously in (41), mGluR5 complex: proteins reported previously in (45). The overlap of the proteins was analysed using VennDIS (75). Major components of the PSD are shown in Fig. 2A and summarized in detail in other review articles (2–4, 8–10). The exterior side of the PSD is enriched in neurotransmitter receptors and trans-synaptic adhesion molecules embedded in the plasma membrane. Two types of ionotropic glutamate receptors, N-methyl-D-aspartate receptors (NMDARs) and α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), that mediate cation influx within neurons, are highly enriched in the PSD (2). Cell adhesion molecules, such as N-cadherin, neuroligins (NLGNs) (19), leucine-rich repeat transmembrane proteins (LRRTMs) (20) and Eph receptors (21) function as bridges towards a presynaptic side and play essential roles in synapse formation and plasticity. Beneath the receptors and adhesion molecules, there is a matrix of scaffolding proteins organized by protein–protein interactions. These scaffolding proteins include membrane-associated guanylate kinase (MAGUK), guanylate kinase-associated protein (GKAP), SH3 and multiple ankyrin repeat domains protein (SHANK) and HOMER. MAGUKs can be classified into several subfamilies, including the PSD-95 subfamily (4). The PSD-95 subfamily (also known as discs large homologue (DLG) subfamily) is composed of SAP97 (DLG1), PSD-93 (DLG2), SAP102 (DLG3) and PSD-95 (DLG4) (22). These proteins have three PSD-95/Discs large/Zona occludens-1 (PDZ) domains. PDZ1 and PDZ2 interact with GluN2 subunits of NMDAR, whereas PDZ3 interacts with cytoplasmic tails of NLGNs (23). In addition, PSD-95 indirectly associates with AMPAR through Stargazin (24). GKAP (also known as SAP90/PSD-95-associated protein 1, SAPAP1 and discs large homologue-associated protein 1, DLGAP1) is a family of four proteins that interact with guanylate kinase (GK) domains of the PSD-95 family proteins (25–27) and PDZ domains of SHANK proteins (28). SHANK proteins then bind to actin cytoskeletal proteins and Homer proteins, which in turn interact with metabotropic glutamate receptors (10, 29). As well as these scaffold proteins, there are several signalling molecules that are abundant in the PSD. Calcium/calmodulin-dependent protein kinase II (CaMKII) is a highly abundant kinase that accounts for 2–6% of total proteins in the PSD of rat forebrain (30). CaMKII is composed of 12 catalytically active subunits encoded by 4 different genes. CAMK2A–D encodes CaMKIIα–CaMKIIδ subunits, respectively. CaMKII directly or indirectly associates with filamentous actin (F-actin). In addition, Ca2+ influx through NMDAR promotes the interaction of CaMKII with a GluN2B subunit of NMDAR and results in the accumulation of CaMKII at the PSD. This accumulation is important for long-term potentiation (LTP) (30). Synaptic GTPase-activating protein (SYNGAP) is another abundant protein in the PSD. SYNGAP is associated with PSD-95 and acts as a negative regulator of Ras small GTPase. CaMKII-mediated phosphorylation of SYNGAP causes dissociation of SYNGAP from PSD-95, resulting in the dispersion of SYNGAP from spines and activation of Ras (31). Another small GTPase regulatory factor that interacts with PSD-95 is Kalirin-7. Kalirin-7 acts as a guanine nucleotide exchange factor for Rac GTPase (4). CaMKII phosphorylates and activates Kalirin-7 and promotes F-actin polymerization (30). Activity-regulated cytoskeleton-associated protein (Arc) (also known as activity-regulated gene of 3.1 kb (Arg3.1)) controls synaptic strength by facilitating internalization of AMPAR through endocytosis. Arc can also interact with PSD-95 and CaMKIIα (32, 33). In addition, Arc preferentially interacts with CaMKIIβ that is not bound to calmodulin (23). β-catenin is a cytoplasmic binding partner of N-cadherin, which is involved in Wnt signalling (34). The activity-induced inter-spine competition for β-catenin is important for spine pruning and maturation (35). Fragile X mental retardation protein (FMRP) is a protein encoded by the FMR1 gene, a gene responsible for fragile X syndrome. FMRP is an RNA-binding protein that represses translation of target mRNA (36). A total of 842 transcripts were identified as FMRP targets, including about 250 transcripts encoding PSD proteins (Fig. 4) (36). Cytoplasmic FMRP interacting protein 1 (CYFIP1) is a PSD protein that interacts with FMRP and participates in FMRP-mediated translational regulation (37). Fig. 4 View largeDownload slide Overlap between PSD genes, FMRP targets and ASD genes. Venn diagram illustrating the overlap of three gene sets. PSD ‘total’: Genes encoding PSD proteins identified both in human and mouse brains (17, 18), FMRP targets: genes whose mRNAs are targets of FMRP (30), SFARI autism genes: genes related to ASD listed in SFARI (Database updated on July 10, 2017). The overlap of the proteins was analysed using VennDIS (75). Fig. 4 View largeDownload slide Overlap between PSD genes, FMRP targets and ASD genes. Venn diagram illustrating the overlap of three gene sets. PSD ‘total’: Genes encoding PSD proteins identified both in human and mouse brains (17, 18), FMRP targets: genes whose mRNAs are targets of FMRP (30), SFARI autism genes: genes related to ASD listed in SFARI (Database updated on July 10, 2017). The overlap of the proteins was analysed using VennDIS (75). In addition to the PSD proteome, the composition of a protein complex in the PSD has also been studied (Fig. 2A and B). NMDARs and scaffold proteins in the PSD can form protein complexes with MDa in mass (38). An NMDAR complex (also known as MAGUK-associated signalling complex, MASC) can be isolated by a peptide affinity method using a PDZ-binding domain of an NMDAR subunit 2 (39). The mammalian NMDAR complex is composed of approximately 200 proteins. Among them, 52 proteins were identified in both mouse and human brains (samples were derived from neurosurgical biopsy) (Fig. 2B) (17, 40). The composition of the AMPAR complex has also been analysed and 34 proteins were found as high-confidence constituents (41). When compared with NMDAR stably embedded in the PSD, AMPAR is relatively mobile and soluble with mild detergents (41). Relatively few overlaps of proteins between PSD and AMPAR complexes are consistently found (Fig. 2B). Proteomic analysis of the tandem affinity purification (TAP)-tagged PSD-95 complex, which was purified from PSD-95-TAP knockin mouse brain, resulted in identification of 118 proteins (42). Among them, 48 proteins overlapped with the PSD-95 complex that was affinity-purified from the PSD (43). Analysis of mGluR isolated from rat brain lysates identified 71 proteins co-immunoprecipitated with mGluR5 (44). More recently, an mGluR5 complex isolated from the mouse cortex and hippocampus was analysed using an mGluR5 knockout mouse brain as a negative control to exclude false positives (45). As a result, 13 proteins were identified. Analysis of an Arc protein complex identified 28 Arc-interacting proteins (32). There is considerable overlap among the composition of NMDAR, PSD-95 and Arc complexes. These findings are consistent with their physical associations (Fig. 2A and B). A recent study showed 2,876 proteins interact with 3 PSD scaffold proteins and 15 scaffold interactors (46). Differences of PSD protein composition among different brain regions, species and physiological conditions It is known that there is considerable molecular heterogeneity of the PSD among different brain regions. An earlier study showed the ultrastructural and biochemical differences of the PSD in the cerebral cortex, midbrain and cerebellum (11). Comparison of the PSD proteome between the forebrain and cerebellum identified a significant change of abundance in 43 proteins, including a higher expression of NMDAR subunit 2B in the forebrain (47). Another study compared protein abundance and phosphorylation status of PSD proteins in the cortex, midbrain, cerebellum and hippocampus (Fig. 3A) (48). This study showed high abundance of kinases and phosphatases and phosphorylated peptides in the hippocampal PSD (Fig. 3A). Fig. 3 View largeDownload slide Differences of PSD protein composition among different brain regions, species and physiological conditions. (A) Top 10 PSD proteins that are more abundant in indicated brain regions compared with the other regions (48). The proteins identified in two replicates are listed. (B) Comparison of the postsynaptic proteins among different species. Proteins involved in semaphorin-mediated axon guidance are abundant in human PSD compared with mouse PSD (18). Many proteins related to vesicle-mediated intracellular trafficking are absent in zebrafish PSD, whereas they can be detected in mouse PSD (50). Mouse NMDAR complex includes greater number of upstream signalling molecules (receptors, scaffolds, kinases etc.) compared with fly NMDAR complex (49) (C) Modulation of phosphorylation status of PSD proteins during LTD and LTP. The number of phosphorylated or dephosphorylated PSD proteins upon indicated stimuli is shown with representative proteins reported in these studies (51, 52). (D) Difference in PSD between wake and sleep states (figure modified from Ref. (47)). PSD targeting of Homer1a during a sleep state causes disassembly of the mGluR5-Homer1L-IP3R complex and dissociation of IP3R and PKCγ from PSD (53). Fig. 3 View largeDownload slide Differences of PSD protein composition among different brain regions, species and physiological conditions. (A) Top 10 PSD proteins that are more abundant in indicated brain regions compared with the other regions (48). The proteins identified in two replicates are listed. (B) Comparison of the postsynaptic proteins among different species. Proteins involved in semaphorin-mediated axon guidance are abundant in human PSD compared with mouse PSD (18). Many proteins related to vesicle-mediated intracellular trafficking are absent in zebrafish PSD, whereas they can be detected in mouse PSD (50). Mouse NMDAR complex includes greater number of upstream signalling molecules (receptors, scaffolds, kinases etc.) compared with fly NMDAR complex (49) (C) Modulation of phosphorylation status of PSD proteins during LTD and LTP. The number of phosphorylated or dephosphorylated PSD proteins upon indicated stimuli is shown with representative proteins reported in these studies (51, 52). (D) Difference in PSD between wake and sleep states (figure modified from Ref. (47)). PSD targeting of Homer1a during a sleep state causes disassembly of the mGluR5-Homer1L-IP3R complex and dissociation of IP3R and PKCγ from PSD (53). Grant and colleagues compared the composition of postsynaptic molecules in different species (Fig. 3B) (7, 17, 18, 49, 50). Genomic and proteomic analyses of the mouse PSD, and mouse and fly NMDAR complexes revealed that vertebrates have greater numbers of upstream signalling molecules (receptors, scaffolds, kinases etc.) compared with invertebrates, indicating a greater signalling complexity in vertebrates (Fig. 3B) (49). Analysis of the PSD in zebrafish showed that ultrastructural features of PSDs are shared across vertebrates (50). Although ∼1,000 proteins are shared across vertebrates, several subsets of proteins, including those involved in intracellular vesicle biogenesis, are absent in zebrafish PSDs, suggesting biological differences of PSDs between fish and mammals (Fig. 3B) (50). Comparison of mouse and human PSD proteomes showed a large compositional overlap and a broadly similar profile of abundance within these species (17, 18). Nevertheless, there were some differences. For example, typical PSD scaffold proteins (e.g. PSD-95, GKAP and SHANKs) and the subunits of AMPAR and NMDAR are more abundant in mouse PSDs, whereas proteins involved in semaphorin-mediated axon guidance are more abundant in human PSDs (Fig. 3B). The PSD is a densely packed protein complex, but also mobile. PSD proteins are regulated by protein modification such as phosphorylation and undergo assembly and disassembly, clustering and diffusion and membrane insertion and removal processes in response to various neuronal stimuli (4). Exposure of mouse hippocampal brain slices to NMDA induced long-term depression (LTD) and caused changes in the phosphorylation status of 127 PSD proteins (phosphorylation in 36 proteins and dephosphorylation in 101 proteins) likely through modulation of 9 PSD kinases (Fig. 3C) (51). On the other hand, induction of LTP induced by high-frequency, tetanic stimulation of Schaffer collateral fibre synapses in the CA1 region altered phosphorylation status of 222 PSD proteins (phosphorylation in 129 proteins and dephosphorylation in 135 proteins) (Fig. 3C) (52). The comparison of PSD compositions between awake and sleep states has recently shown that PSD targeting of Homer1a during a sleep state causes disassembly of the mGluR5-Homer1L-IP3R complex, which contributes to synaptic AMPAR removal and memory consolidation during a sleep state (Fig. 3D) (53). Differences in PSD composition are also found among different developmental stages. A recent study reported differences in a PSD scaffold protein complex at four different developmental stages. In this study PSD-95, GKAP and SHANK3 were immunoprecipitated from the prefrontal cortex of mice at embryonic day 14 (E14), postnatal day 7 (P7), P14 and an adult stage (46). In E14 protein complexes, PSD-95 and GKAP interact with each other, but not with a SHANK protein complex. After P7, interaction among PSD-95, GKAP and SHANK3 complexes can be detected, followed by full scaffold assembly at an adult stage (46). Another study reported the maturation of ∼1.5 MDa NMDAR supercomplexes during postnatal development (38). PSD proteins in neurodevelopmental disorders PSD proteins are related to various neuropsychiatric diseases. An initial study of the human PSD proteome identified proteins related to more than 100 diseases described in the International Classification of Diseases 10th Revision (ICD-10) (13). Recent genetic studies further extended our knowledge of the relationship between PSD proteins and neuropsychiatric disorders, especially for ASD and schizophrenia (6, 54–57). In addition to genetic involvement, changes in the PSD integrity are found in postmortem brains in several diseases, including schizophrenia, bipolar disorder and Alzheimer’s disease (58–60). ASD is a neurodevelopmental disorder and affects 1 in 68 children under 8 years of age in the USA (61, 62). Patients with ASD manifest deficits in two core domains; dysfunction in social interaction and communication, and the presence of repetitive and restricted behaviour (62). Genetic studies showed that ASD is highly heritable, suggesting that there is a considerable genetic contribution (61–63). Simons Foundation Autism Research Initiative (SFARI) summarizes genes implicated in ASD (https://www.sfari.org/). Currently (Database updated on July 10, 2017) 910 genes are listed here (Fig. 4). Genes associated with ASD include those involved in protein translation, Wnt signalling and synaptic signalling (62, 64). They include several genes encoding typical PSD proteins. For example, GRIN2B (which encodes NMDAR subunit GluN2B), SYNGAP1, CTNNB1 (β-catenin), NLGNs and SHANKs are reported as autism risk genes (Fig. 2A) (62, 64). Rare variants of NLGN3 and NLGN4 were first reported as a genetic aetiology of ASD (65) and other variants in NLGN1 have also been found in patients with ASD (66). The SHANK3 gene was a missing gene in Phelan-McDermid (22q13.3 deletion) syndrome, a disorder characterized by ASD-like behaviour, hypotonia and delayed speech and its rare variants, as well as those of SHANK1 and SHANK2, have also been found in ASD (10). Mutations affecting the FMRP-CYFIP1 complex, which regulates translation of various PSD proteins, increase the risk of ASD (Figs 2A and 4) (62–64). An exome sequencing study for patients with ASD showed 107 autism risk genes, in which genes encoding PSD proteins are significantly enriched, as well as FMRP targets and genes involved in chromatin remodeling (54). Phosphorylation signalling in the PSD seems to be related to ASD. Among the entire PSD proteins, proteins that exhibit phosphorylation-dependent regulation by LTP are particularly enriched in the proteins encoded by genes mutated in ASD (52). These reports suggest a close relationship between ASD and the PSD in light of postsynaptic architectures and their signalling. To study mechanistic insights of ASD, the mouse model is a useful tool. Different kinds of mouse models, such as knockout mice for ASD-related genes and knockin mice for rare variants found in patients, have been available (62). These mice show ASD like features, such as impaired social interaction and communication, and repetitive behaviour (62, 67). They also show synaptic phenotypes, such as alteration in spine density, size, shape and dynamics or defective synaptic plasticity and transmission (1, 62, 68, 69). Schizophrenia is a psychiatric disorder with an incidence of about one percent of the population. It is characterized with diverse psychopathology, including delusions, hallucinations, impaired motivation, reduction in spontaneous speech and social withdrawal (70). Schizophrenia is also heritable (70). In schizophrenia patients, mutations have been reported in genes encoding a range of synaptic proteins including components of the PSD, which are important for fine-tuning synaptic transmission (70, 71). Exome sequencing studies demonstrated that mutations found in schizophrenia are enriched in PSD components, as well as genes whose mRNAs are targets of FMRP (56, 57). These studies also showed that the signalling complexes formed by NMDAR, PSD-95 and Arc are particularly enriched (Fig. 2A and B) (56, 57). In addition, phosphorylation signalling in the PSD particularly shows a close relationship with schizophrenia, as well as ASD (52). The mutated genes found in schizophrenia overlap with those in ASD (54–56). For instance, whole exome sequencing of patients with ASD identified de novo mutations in 353 genes (nonsense, frameshift and splice site mutation) (55). Nine of these genes overlap with 93 mutated genes reported in schizophrenia patients (55). Changes in the PSD integrity are reported in schizophrenia patients. Proteomic analysis of the PSD isolated from the anterior cingulate cortex in postmortem brains identified 143 differentially expressed proteins in patients with schizophrenia (58). These proteins are enriched in pathways involved in endocytosis, LTP and calcium signalling (58). These studies indicate a close relationship between schizophrenia and defective postsynaptic signalling through PSD proteins. Concluding remarks and future perspectives The PSD has been extensively studied since the first report of a PSD observation using electron microscopy (72). Proteomic studies showed its composition. Bioinformatics and systems biology for systematic and big data obtained by proteome enabled us to further understand it. Studies in molecular biology and biochemistry showed networks of protein interactions within the PSD. Studies using cultured neurons and model organisms showed its functional properties. Recent genetic studies revealed their relationship with diseases, including psychiatric disorders such as ASD and schizophrenia. In the future, it would be important to study the function of PSD proteins in the specific brain regions and their circuits, because the function of synaptic molecules at a circuit level should be essential for understanding in vivo brain functions, such as behaviour and the pathophysiology of psychiatric disorders. Animal models of psychiatric disorders with PSD gene mutations would be a strong tool to address these issues, although the phenotype of these animals may not be simple in some cases. As mentioned above, for example, there is a considerable overlap between ASD risk genes and schizophrenia risk genes, which include various genes encoding PSD proteins. It seems to be consistent with some shared symptoms between these two disorders, such as theory of mind deficits (73). Of course, ASD and schizophrenia are not phenotypically identical. ASD is incompatible with positive symptoms of schizophrenia, such as delusions and hallucinations (73). In addition, the symptoms of ASD first appear during early life while schizophrenic symptoms typically appear during adolescence (73). Therefore, it seems that mutation of the identical gene can result in different outcomes. One possible explanation for this phenomenon is functional alteration of synaptic proteins due to temporally defined molecular interactions during development, as discussed in a previous report (74). It will therefore be necessary that we take an integrated approach to understand how PSD proteins are regulated both spatially at a circuit level and temporally during the developmental stage. Acknowledgements We thank Qalam Eusuf for comments on the article. Funding This work was supported in part by KAKENHI (16H06316, 16H06463 and 16K13110), Japan Society of Promotion of Science (JSPS) and Ministry of Education, Culture, Sports, Science and Technology and the Takeda Science Foundation. T.K. was supported by Grant-in-Aid for JSPS Fellows (16J04376). Conflict of Interest None declared. References 1 Penzes P., Cahill M.E., Jones K.A., VanLeeuwen J.E., Woolfrey K.M. ( 2011) Dendritic spine pathology in neuropsychiatric disorders. Nat. Neurosci.  14, 285– 293 Google Scholar CrossRef Search ADS PubMed  2 Sheng M., Hoogenraad C.C. ( 2007) The postsynaptic architecture of excitatory synapses, a more quantitative view. Annu. Rev. 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Proteomics.  15, 1239– 1244 Google Scholar CrossRef Search ADS PubMed  Abbreviations Abbreviations AMPAR α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor Arc activity-regulated cytoskeleton-associated protein Arg3.1 activity-regulated gene of 3.1 kb CaMKII Calcium/calmodulin-dependent protein kinase II F-actin filamentous actin FMRP fragile X mental retardation protein GK guanylate kinase GKAP guanylate kinase-associated protein ICD-10 International Classification of Diseases 10th Revision LRRTM leucine-rich repeat transmembrane protein LTD long-term depression LTP long-term potentiation MAGUK membrane-associated guanylate kinase MASC MAGUK-associated signalling complex mGluR metabotropic glutamate receptor NMDAR N-methyl-D-aspartate receptor PSD postsynaptic density SAPAP SAP90/PSD95-associated protein SFARI Simons Foundation Autism Research Initiative SHANK SH3 and multiple ankyrin repeat domains protein SYNGAP synaptic GTPase-activating protein TAP tandem affinity purification © The Author(s) 2018. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Biochemistry Oxford University Press

Postsynaptic density proteins and their involvement in neurodevelopmental disorders

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved
ISSN
0021-924X
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1756-2651
D.O.I.
10.1093/jb/mvy022
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Abstract

Abstract Synaptic connections are essential for neural circuits in order to convey brain functions. The postsynaptic density (PSD) is a huge protein complex associated with postsynaptic membranes of excitatory synapses. In mammals, the PSD is composed of more than 1,000 proteins including receptors, scaffold proteins, signalling enzymes and cytoskeletal proteins. PSD proteins are crucial for synaptic transmission and plasticity. Proteomic studies have revealed the composition of PSD proteins in various species, brain regions and specific physiological conditions. Abnormalities with PSD proteins are linked to various neuropsychiatric diseases including neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Here, we review different kinds of proteomic studies of the PSD and the involvement of PSD proteins in physiological and pathological conditions. autism, proteomics, PSD (postsynaptic density), PSD-95, schizophrenia Neurons connect to each other to form neural networks via junctions called synapses. In the mammalian brain, most glutamatergic excitatory synapses are situated on tiny protrusions along dendrites, called dendritic spines (Fig. 1) (1, 2). The postsynaptic density (PSD) is an electron-dense structure beneath the postsynaptic membrane of excitatory synapses and is usually located at the tip of the dendritic spine (Fig. 1) (2–4). The PSD is composed of a densely packed protein complex that typically forms a disk-like structure with a diameter of 200–800 nm and a thickness of 30–60 nm in the mammalian brain (2–4). Proteomic studies have revealed that PSDs are composed of thousands of different proteins, including neurotransmitter receptors, cell adhesion molecules, scaffold proteins, signalling enzymes, cytoskeleton proteins and membrane trafficking proteins (2, 4). It is now known that mutations of many PSD proteins are associated with human neurological and psychiatric diseases, including autism spectrum disorder (ASD, hereafter) and schizophrenia (5). Recent large-scale genomic studies have extended the knowledge about the genetic architecture of psychiatric disorders and showed an excess of disruptive mutations in ASD and schizophrenia in several postsynaptic gene sets (6). Whereas there are comprehensive review articles regarding this topic (7–10), in this review, we summarize previous studies of PSD proteome and the involvement of PSD proteins in psychiatric diseases. Fig. 1 View largeDownload slide Dendritic spines and PSD. Mouse hippocampal neurons transfected with PSD-95-GFP (green) and dsRed (red). Dendritic spines are small protrusions along dendrites. PSD-95 (PSD marker) is localized mainly to the spine tip. Fig. 1 View largeDownload slide Dendritic spines and PSD. Mouse hippocampal neurons transfected with PSD-95-GFP (green) and dsRed (red). Dendritic spines are small protrusions along dendrites. PSD-95 (PSD marker) is localized mainly to the spine tip. Core components in PSDs PSDs can be purified from brain samples by differential centrifugation and sucrose density gradient centrifugation, followed by detergent extraction by Triton X-100, which does not solubilize PSDs (11). This method is widely used for proteomic analysis of the PSD. Studies in the early 2000s identified most of the major PSD components through mass spectrometry-based analysis of purified PSD fractions (12–16). More recently, the dataset of the mammalian PSD proteome has been updated (17, 18) and summarized on the Genes to Cognition website (http://www.genes2cognition.org/), together with other proteome datasets published by this group. In mouse and human brains, 1,556 and 1,461 proteins were identified as PSD proteins, respectively, and 1,019 proteins were identified in both species (17, 18) (Fig. 2A and B). Among them, 984 proteins in mouse and 748 proteins in human (547 in both) were identified in triplicate and defined as ‘consensus’ PSD proteins (17, 18) (Fig. 2A and B). Fig. 2 View largeDownload slide Major PSD proteins. (A) Well-known proteins in the PSD. The exterior side is enriched in glutamate receptors (NMDAR and AMPAR) and adhesion molecules (N-Cadherin, NLGN, LRRTM and EphR). NMDAR and AMPAR are associated with a matrix of scaffold proteins including PSD-95, GKAP, SHANK and Homer. PSD-95 also interacts with NLGN and small GTPase regulators SYNGAP and Kalirin-7. SHANK is associated with F-actin through Cortactin. Homer interacts with mGluR. CaMKII kinase is associated with F-actin and NMDAR. Arc interacts with CaMKII. FMRP-CYFIP1 complex represses translation of target mRNA. (B) Overlap of protein composition between each protein complex and indicated subsets of proteins in the PSD. PSD: consensus PSD proteins and total PSD proteins identified both in human and mouse brain are shown (17, 18), NMDAR complex: GluN2B peptide interacting proteins identified both in human (biopsy) and mouse brain are shown (16, 40), PSD-95 complex: PSD-95 interacting proteins identified in two independent experiments are shown (42, 43), Arc complex: proteins reported previously in (32), AMPAR complex: proteins reported previously in (41), mGluR5 complex: proteins reported previously in (45). The overlap of the proteins was analysed using VennDIS (75). Fig. 2 View largeDownload slide Major PSD proteins. (A) Well-known proteins in the PSD. The exterior side is enriched in glutamate receptors (NMDAR and AMPAR) and adhesion molecules (N-Cadherin, NLGN, LRRTM and EphR). NMDAR and AMPAR are associated with a matrix of scaffold proteins including PSD-95, GKAP, SHANK and Homer. PSD-95 also interacts with NLGN and small GTPase regulators SYNGAP and Kalirin-7. SHANK is associated with F-actin through Cortactin. Homer interacts with mGluR. CaMKII kinase is associated with F-actin and NMDAR. Arc interacts with CaMKII. FMRP-CYFIP1 complex represses translation of target mRNA. (B) Overlap of protein composition between each protein complex and indicated subsets of proteins in the PSD. PSD: consensus PSD proteins and total PSD proteins identified both in human and mouse brain are shown (17, 18), NMDAR complex: GluN2B peptide interacting proteins identified both in human (biopsy) and mouse brain are shown (16, 40), PSD-95 complex: PSD-95 interacting proteins identified in two independent experiments are shown (42, 43), Arc complex: proteins reported previously in (32), AMPAR complex: proteins reported previously in (41), mGluR5 complex: proteins reported previously in (45). The overlap of the proteins was analysed using VennDIS (75). Major components of the PSD are shown in Fig. 2A and summarized in detail in other review articles (2–4, 8–10). The exterior side of the PSD is enriched in neurotransmitter receptors and trans-synaptic adhesion molecules embedded in the plasma membrane. Two types of ionotropic glutamate receptors, N-methyl-D-aspartate receptors (NMDARs) and α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), that mediate cation influx within neurons, are highly enriched in the PSD (2). Cell adhesion molecules, such as N-cadherin, neuroligins (NLGNs) (19), leucine-rich repeat transmembrane proteins (LRRTMs) (20) and Eph receptors (21) function as bridges towards a presynaptic side and play essential roles in synapse formation and plasticity. Beneath the receptors and adhesion molecules, there is a matrix of scaffolding proteins organized by protein–protein interactions. These scaffolding proteins include membrane-associated guanylate kinase (MAGUK), guanylate kinase-associated protein (GKAP), SH3 and multiple ankyrin repeat domains protein (SHANK) and HOMER. MAGUKs can be classified into several subfamilies, including the PSD-95 subfamily (4). The PSD-95 subfamily (also known as discs large homologue (DLG) subfamily) is composed of SAP97 (DLG1), PSD-93 (DLG2), SAP102 (DLG3) and PSD-95 (DLG4) (22). These proteins have three PSD-95/Discs large/Zona occludens-1 (PDZ) domains. PDZ1 and PDZ2 interact with GluN2 subunits of NMDAR, whereas PDZ3 interacts with cytoplasmic tails of NLGNs (23). In addition, PSD-95 indirectly associates with AMPAR through Stargazin (24). GKAP (also known as SAP90/PSD-95-associated protein 1, SAPAP1 and discs large homologue-associated protein 1, DLGAP1) is a family of four proteins that interact with guanylate kinase (GK) domains of the PSD-95 family proteins (25–27) and PDZ domains of SHANK proteins (28). SHANK proteins then bind to actin cytoskeletal proteins and Homer proteins, which in turn interact with metabotropic glutamate receptors (10, 29). As well as these scaffold proteins, there are several signalling molecules that are abundant in the PSD. Calcium/calmodulin-dependent protein kinase II (CaMKII) is a highly abundant kinase that accounts for 2–6% of total proteins in the PSD of rat forebrain (30). CaMKII is composed of 12 catalytically active subunits encoded by 4 different genes. CAMK2A–D encodes CaMKIIα–CaMKIIδ subunits, respectively. CaMKII directly or indirectly associates with filamentous actin (F-actin). In addition, Ca2+ influx through NMDAR promotes the interaction of CaMKII with a GluN2B subunit of NMDAR and results in the accumulation of CaMKII at the PSD. This accumulation is important for long-term potentiation (LTP) (30). Synaptic GTPase-activating protein (SYNGAP) is another abundant protein in the PSD. SYNGAP is associated with PSD-95 and acts as a negative regulator of Ras small GTPase. CaMKII-mediated phosphorylation of SYNGAP causes dissociation of SYNGAP from PSD-95, resulting in the dispersion of SYNGAP from spines and activation of Ras (31). Another small GTPase regulatory factor that interacts with PSD-95 is Kalirin-7. Kalirin-7 acts as a guanine nucleotide exchange factor for Rac GTPase (4). CaMKII phosphorylates and activates Kalirin-7 and promotes F-actin polymerization (30). Activity-regulated cytoskeleton-associated protein (Arc) (also known as activity-regulated gene of 3.1 kb (Arg3.1)) controls synaptic strength by facilitating internalization of AMPAR through endocytosis. Arc can also interact with PSD-95 and CaMKIIα (32, 33). In addition, Arc preferentially interacts with CaMKIIβ that is not bound to calmodulin (23). β-catenin is a cytoplasmic binding partner of N-cadherin, which is involved in Wnt signalling (34). The activity-induced inter-spine competition for β-catenin is important for spine pruning and maturation (35). Fragile X mental retardation protein (FMRP) is a protein encoded by the FMR1 gene, a gene responsible for fragile X syndrome. FMRP is an RNA-binding protein that represses translation of target mRNA (36). A total of 842 transcripts were identified as FMRP targets, including about 250 transcripts encoding PSD proteins (Fig. 4) (36). Cytoplasmic FMRP interacting protein 1 (CYFIP1) is a PSD protein that interacts with FMRP and participates in FMRP-mediated translational regulation (37). Fig. 4 View largeDownload slide Overlap between PSD genes, FMRP targets and ASD genes. Venn diagram illustrating the overlap of three gene sets. PSD ‘total’: Genes encoding PSD proteins identified both in human and mouse brains (17, 18), FMRP targets: genes whose mRNAs are targets of FMRP (30), SFARI autism genes: genes related to ASD listed in SFARI (Database updated on July 10, 2017). The overlap of the proteins was analysed using VennDIS (75). Fig. 4 View largeDownload slide Overlap between PSD genes, FMRP targets and ASD genes. Venn diagram illustrating the overlap of three gene sets. PSD ‘total’: Genes encoding PSD proteins identified both in human and mouse brains (17, 18), FMRP targets: genes whose mRNAs are targets of FMRP (30), SFARI autism genes: genes related to ASD listed in SFARI (Database updated on July 10, 2017). The overlap of the proteins was analysed using VennDIS (75). In addition to the PSD proteome, the composition of a protein complex in the PSD has also been studied (Fig. 2A and B). NMDARs and scaffold proteins in the PSD can form protein complexes with MDa in mass (38). An NMDAR complex (also known as MAGUK-associated signalling complex, MASC) can be isolated by a peptide affinity method using a PDZ-binding domain of an NMDAR subunit 2 (39). The mammalian NMDAR complex is composed of approximately 200 proteins. Among them, 52 proteins were identified in both mouse and human brains (samples were derived from neurosurgical biopsy) (Fig. 2B) (17, 40). The composition of the AMPAR complex has also been analysed and 34 proteins were found as high-confidence constituents (41). When compared with NMDAR stably embedded in the PSD, AMPAR is relatively mobile and soluble with mild detergents (41). Relatively few overlaps of proteins between PSD and AMPAR complexes are consistently found (Fig. 2B). Proteomic analysis of the tandem affinity purification (TAP)-tagged PSD-95 complex, which was purified from PSD-95-TAP knockin mouse brain, resulted in identification of 118 proteins (42). Among them, 48 proteins overlapped with the PSD-95 complex that was affinity-purified from the PSD (43). Analysis of mGluR isolated from rat brain lysates identified 71 proteins co-immunoprecipitated with mGluR5 (44). More recently, an mGluR5 complex isolated from the mouse cortex and hippocampus was analysed using an mGluR5 knockout mouse brain as a negative control to exclude false positives (45). As a result, 13 proteins were identified. Analysis of an Arc protein complex identified 28 Arc-interacting proteins (32). There is considerable overlap among the composition of NMDAR, PSD-95 and Arc complexes. These findings are consistent with their physical associations (Fig. 2A and B). A recent study showed 2,876 proteins interact with 3 PSD scaffold proteins and 15 scaffold interactors (46). Differences of PSD protein composition among different brain regions, species and physiological conditions It is known that there is considerable molecular heterogeneity of the PSD among different brain regions. An earlier study showed the ultrastructural and biochemical differences of the PSD in the cerebral cortex, midbrain and cerebellum (11). Comparison of the PSD proteome between the forebrain and cerebellum identified a significant change of abundance in 43 proteins, including a higher expression of NMDAR subunit 2B in the forebrain (47). Another study compared protein abundance and phosphorylation status of PSD proteins in the cortex, midbrain, cerebellum and hippocampus (Fig. 3A) (48). This study showed high abundance of kinases and phosphatases and phosphorylated peptides in the hippocampal PSD (Fig. 3A). Fig. 3 View largeDownload slide Differences of PSD protein composition among different brain regions, species and physiological conditions. (A) Top 10 PSD proteins that are more abundant in indicated brain regions compared with the other regions (48). The proteins identified in two replicates are listed. (B) Comparison of the postsynaptic proteins among different species. Proteins involved in semaphorin-mediated axon guidance are abundant in human PSD compared with mouse PSD (18). Many proteins related to vesicle-mediated intracellular trafficking are absent in zebrafish PSD, whereas they can be detected in mouse PSD (50). Mouse NMDAR complex includes greater number of upstream signalling molecules (receptors, scaffolds, kinases etc.) compared with fly NMDAR complex (49) (C) Modulation of phosphorylation status of PSD proteins during LTD and LTP. The number of phosphorylated or dephosphorylated PSD proteins upon indicated stimuli is shown with representative proteins reported in these studies (51, 52). (D) Difference in PSD between wake and sleep states (figure modified from Ref. (47)). PSD targeting of Homer1a during a sleep state causes disassembly of the mGluR5-Homer1L-IP3R complex and dissociation of IP3R and PKCγ from PSD (53). Fig. 3 View largeDownload slide Differences of PSD protein composition among different brain regions, species and physiological conditions. (A) Top 10 PSD proteins that are more abundant in indicated brain regions compared with the other regions (48). The proteins identified in two replicates are listed. (B) Comparison of the postsynaptic proteins among different species. Proteins involved in semaphorin-mediated axon guidance are abundant in human PSD compared with mouse PSD (18). Many proteins related to vesicle-mediated intracellular trafficking are absent in zebrafish PSD, whereas they can be detected in mouse PSD (50). Mouse NMDAR complex includes greater number of upstream signalling molecules (receptors, scaffolds, kinases etc.) compared with fly NMDAR complex (49) (C) Modulation of phosphorylation status of PSD proteins during LTD and LTP. The number of phosphorylated or dephosphorylated PSD proteins upon indicated stimuli is shown with representative proteins reported in these studies (51, 52). (D) Difference in PSD between wake and sleep states (figure modified from Ref. (47)). PSD targeting of Homer1a during a sleep state causes disassembly of the mGluR5-Homer1L-IP3R complex and dissociation of IP3R and PKCγ from PSD (53). Grant and colleagues compared the composition of postsynaptic molecules in different species (Fig. 3B) (7, 17, 18, 49, 50). Genomic and proteomic analyses of the mouse PSD, and mouse and fly NMDAR complexes revealed that vertebrates have greater numbers of upstream signalling molecules (receptors, scaffolds, kinases etc.) compared with invertebrates, indicating a greater signalling complexity in vertebrates (Fig. 3B) (49). Analysis of the PSD in zebrafish showed that ultrastructural features of PSDs are shared across vertebrates (50). Although ∼1,000 proteins are shared across vertebrates, several subsets of proteins, including those involved in intracellular vesicle biogenesis, are absent in zebrafish PSDs, suggesting biological differences of PSDs between fish and mammals (Fig. 3B) (50). Comparison of mouse and human PSD proteomes showed a large compositional overlap and a broadly similar profile of abundance within these species (17, 18). Nevertheless, there were some differences. For example, typical PSD scaffold proteins (e.g. PSD-95, GKAP and SHANKs) and the subunits of AMPAR and NMDAR are more abundant in mouse PSDs, whereas proteins involved in semaphorin-mediated axon guidance are more abundant in human PSDs (Fig. 3B). The PSD is a densely packed protein complex, but also mobile. PSD proteins are regulated by protein modification such as phosphorylation and undergo assembly and disassembly, clustering and diffusion and membrane insertion and removal processes in response to various neuronal stimuli (4). Exposure of mouse hippocampal brain slices to NMDA induced long-term depression (LTD) and caused changes in the phosphorylation status of 127 PSD proteins (phosphorylation in 36 proteins and dephosphorylation in 101 proteins) likely through modulation of 9 PSD kinases (Fig. 3C) (51). On the other hand, induction of LTP induced by high-frequency, tetanic stimulation of Schaffer collateral fibre synapses in the CA1 region altered phosphorylation status of 222 PSD proteins (phosphorylation in 129 proteins and dephosphorylation in 135 proteins) (Fig. 3C) (52). The comparison of PSD compositions between awake and sleep states has recently shown that PSD targeting of Homer1a during a sleep state causes disassembly of the mGluR5-Homer1L-IP3R complex, which contributes to synaptic AMPAR removal and memory consolidation during a sleep state (Fig. 3D) (53). Differences in PSD composition are also found among different developmental stages. A recent study reported differences in a PSD scaffold protein complex at four different developmental stages. In this study PSD-95, GKAP and SHANK3 were immunoprecipitated from the prefrontal cortex of mice at embryonic day 14 (E14), postnatal day 7 (P7), P14 and an adult stage (46). In E14 protein complexes, PSD-95 and GKAP interact with each other, but not with a SHANK protein complex. After P7, interaction among PSD-95, GKAP and SHANK3 complexes can be detected, followed by full scaffold assembly at an adult stage (46). Another study reported the maturation of ∼1.5 MDa NMDAR supercomplexes during postnatal development (38). PSD proteins in neurodevelopmental disorders PSD proteins are related to various neuropsychiatric diseases. An initial study of the human PSD proteome identified proteins related to more than 100 diseases described in the International Classification of Diseases 10th Revision (ICD-10) (13). Recent genetic studies further extended our knowledge of the relationship between PSD proteins and neuropsychiatric disorders, especially for ASD and schizophrenia (6, 54–57). In addition to genetic involvement, changes in the PSD integrity are found in postmortem brains in several diseases, including schizophrenia, bipolar disorder and Alzheimer’s disease (58–60). ASD is a neurodevelopmental disorder and affects 1 in 68 children under 8 years of age in the USA (61, 62). Patients with ASD manifest deficits in two core domains; dysfunction in social interaction and communication, and the presence of repetitive and restricted behaviour (62). Genetic studies showed that ASD is highly heritable, suggesting that there is a considerable genetic contribution (61–63). Simons Foundation Autism Research Initiative (SFARI) summarizes genes implicated in ASD (https://www.sfari.org/). Currently (Database updated on July 10, 2017) 910 genes are listed here (Fig. 4). Genes associated with ASD include those involved in protein translation, Wnt signalling and synaptic signalling (62, 64). They include several genes encoding typical PSD proteins. For example, GRIN2B (which encodes NMDAR subunit GluN2B), SYNGAP1, CTNNB1 (β-catenin), NLGNs and SHANKs are reported as autism risk genes (Fig. 2A) (62, 64). Rare variants of NLGN3 and NLGN4 were first reported as a genetic aetiology of ASD (65) and other variants in NLGN1 have also been found in patients with ASD (66). The SHANK3 gene was a missing gene in Phelan-McDermid (22q13.3 deletion) syndrome, a disorder characterized by ASD-like behaviour, hypotonia and delayed speech and its rare variants, as well as those of SHANK1 and SHANK2, have also been found in ASD (10). Mutations affecting the FMRP-CYFIP1 complex, which regulates translation of various PSD proteins, increase the risk of ASD (Figs 2A and 4) (62–64). An exome sequencing study for patients with ASD showed 107 autism risk genes, in which genes encoding PSD proteins are significantly enriched, as well as FMRP targets and genes involved in chromatin remodeling (54). Phosphorylation signalling in the PSD seems to be related to ASD. Among the entire PSD proteins, proteins that exhibit phosphorylation-dependent regulation by LTP are particularly enriched in the proteins encoded by genes mutated in ASD (52). These reports suggest a close relationship between ASD and the PSD in light of postsynaptic architectures and their signalling. To study mechanistic insights of ASD, the mouse model is a useful tool. Different kinds of mouse models, such as knockout mice for ASD-related genes and knockin mice for rare variants found in patients, have been available (62). These mice show ASD like features, such as impaired social interaction and communication, and repetitive behaviour (62, 67). They also show synaptic phenotypes, such as alteration in spine density, size, shape and dynamics or defective synaptic plasticity and transmission (1, 62, 68, 69). Schizophrenia is a psychiatric disorder with an incidence of about one percent of the population. It is characterized with diverse psychopathology, including delusions, hallucinations, impaired motivation, reduction in spontaneous speech and social withdrawal (70). Schizophrenia is also heritable (70). In schizophrenia patients, mutations have been reported in genes encoding a range of synaptic proteins including components of the PSD, which are important for fine-tuning synaptic transmission (70, 71). Exome sequencing studies demonstrated that mutations found in schizophrenia are enriched in PSD components, as well as genes whose mRNAs are targets of FMRP (56, 57). These studies also showed that the signalling complexes formed by NMDAR, PSD-95 and Arc are particularly enriched (Fig. 2A and B) (56, 57). In addition, phosphorylation signalling in the PSD particularly shows a close relationship with schizophrenia, as well as ASD (52). The mutated genes found in schizophrenia overlap with those in ASD (54–56). For instance, whole exome sequencing of patients with ASD identified de novo mutations in 353 genes (nonsense, frameshift and splice site mutation) (55). Nine of these genes overlap with 93 mutated genes reported in schizophrenia patients (55). Changes in the PSD integrity are reported in schizophrenia patients. Proteomic analysis of the PSD isolated from the anterior cingulate cortex in postmortem brains identified 143 differentially expressed proteins in patients with schizophrenia (58). These proteins are enriched in pathways involved in endocytosis, LTP and calcium signalling (58). These studies indicate a close relationship between schizophrenia and defective postsynaptic signalling through PSD proteins. Concluding remarks and future perspectives The PSD has been extensively studied since the first report of a PSD observation using electron microscopy (72). Proteomic studies showed its composition. Bioinformatics and systems biology for systematic and big data obtained by proteome enabled us to further understand it. Studies in molecular biology and biochemistry showed networks of protein interactions within the PSD. Studies using cultured neurons and model organisms showed its functional properties. Recent genetic studies revealed their relationship with diseases, including psychiatric disorders such as ASD and schizophrenia. In the future, it would be important to study the function of PSD proteins in the specific brain regions and their circuits, because the function of synaptic molecules at a circuit level should be essential for understanding in vivo brain functions, such as behaviour and the pathophysiology of psychiatric disorders. Animal models of psychiatric disorders with PSD gene mutations would be a strong tool to address these issues, although the phenotype of these animals may not be simple in some cases. As mentioned above, for example, there is a considerable overlap between ASD risk genes and schizophrenia risk genes, which include various genes encoding PSD proteins. It seems to be consistent with some shared symptoms between these two disorders, such as theory of mind deficits (73). Of course, ASD and schizophrenia are not phenotypically identical. ASD is incompatible with positive symptoms of schizophrenia, such as delusions and hallucinations (73). In addition, the symptoms of ASD first appear during early life while schizophrenic symptoms typically appear during adolescence (73). Therefore, it seems that mutation of the identical gene can result in different outcomes. One possible explanation for this phenomenon is functional alteration of synaptic proteins due to temporally defined molecular interactions during development, as discussed in a previous report (74). 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Proteomics.  15, 1239– 1244 Google Scholar CrossRef Search ADS PubMed  Abbreviations Abbreviations AMPAR α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor Arc activity-regulated cytoskeleton-associated protein Arg3.1 activity-regulated gene of 3.1 kb CaMKII Calcium/calmodulin-dependent protein kinase II F-actin filamentous actin FMRP fragile X mental retardation protein GK guanylate kinase GKAP guanylate kinase-associated protein ICD-10 International Classification of Diseases 10th Revision LRRTM leucine-rich repeat transmembrane protein LTD long-term depression LTP long-term potentiation MAGUK membrane-associated guanylate kinase MASC MAGUK-associated signalling complex mGluR metabotropic glutamate receptor NMDAR N-methyl-D-aspartate receptor PSD postsynaptic density SAPAP SAP90/PSD95-associated protein SFARI Simons Foundation Autism Research Initiative SHANK SH3 and multiple ankyrin repeat domains protein SYNGAP synaptic GTPase-activating protein TAP tandem affinity purification © The Author(s) 2018. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

The Journal of BiochemistryOxford University Press

Published: Feb 5, 2018

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