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.
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The synapse proteome is complex, comprising over a thousand conserved proteins, particularly within excitatory synapses.
“In the early 2000s, major advances occurred with the discovery that the synapse proteome is complex, comprising over a thousand conserved proteins, particularly within excitatory synapses [9].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [9]
The PSD comprises over a thousand different proteins in mammals.
“The PSD is characterized by high molecular complexity, comprising over a thousand different proteins in mammals [9].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [9]
Abnormalities in PSD proteins are strongly linked to various neuropsychiatric diseases, including autism spectrum disorder and schizophrenia.
“The integrity and proper function of PSD proteins are paramount, as abnormalities have been strongly linked to various neuropsychiatric diseases, including autism spectrum disorder and schizophrenia [9].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [9]
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“The postsynaptic region of excitatory synapses, referred to as postsynaptic density (PSD), is composed of an array of proteins among which the glutamate N-methylD-aspartate receptor (NMDAR) is anchored to form a multiprotein complex (Kaizuka and Takumi 2018).”
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BackgroundAlteration of synaptic protein composition during developmental synapse maturation
Kaizuka, T., & Takumi, T. (2024) · European Journal of Neuroscience · doi:10.1111/ejn.16304 · Cited by 12 · see citing works
“The GluN2B subunit of the NMDAR binds to PSD-95, whereas the AMPAR associates with PSD-95 through transmembrane AMPAR regulatory proteins (TARPs), including stargazin (Kaizuka & Takumi, 2018; Zhu et al., 2016).”
BackgroundSelf-citationIasevoli, F., Buonaguro, E., Avagliano, C., Barone, A., Eramo, A., Vellucci, L., & de Bartolomeis, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155555 · Cited by 11 · see citing works
“Notably, antipsychotic agents have been found to modulate the expression of glutamatergic genes of the postsynaptic density (PSD), an electron-dense thickening at the surface of the glutamatergic postsynaptic membrane [5–7], actively involved in behavioral disorders’ molecular pathophysiology [8,9].”
BackgroundDąbrowska-Bouta, B., Sulkowski, G., Sałek, M., Frontczak-Baniewicz, M., & Strużyńska, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22063067 · Cited by 10 · see citing works
“In the case of particulate silver, direct dynamic interactions with different proteins are possible which tend to create reversible or irreversible protein coronas [21], thereby temporarily modulating the composition of protein-enriched PSDs.”
BackgroundInfluentialCell‐type‐specific visualisation and biochemical isolation of endogenous synaptic proteins in mice
Zhu, F., Collins, M., Harmse, J., Choudhary, J., Grant, S., & Komiyama, N. (2019) · European Journal of Neuroscience · doi:10.1111/ejn.14597 · Cited by 10 · see citing works
Cell-type specific visualization and biochemical isolation of endogenous synaptic proteins in mice
Zhu, F., Collins, M., Harmse, J., Choudhary, J., Grant, S., & Komiyama, N. (2018) · bioRxiv · doi:10.1101/363614 · Cited by 9
Cullin-RING Ubiquitin Ligases in Neurodevelopment and Neurodevelopmental Disorders
Ashitomi, H., Nakagawa, T., Nakagawa, M., & Hosoi, T. (2025) · Biomedicines · doi:10.3390/biomedicines13040810 · Cited by 11 · see citing works
“…such as glutamate, dopamine, acetylcholine (ACh), and gamma-aminobutyric acid (GABA), which bind to their corresponding receptors in the specialized postsynaptic density (PSD) region of the postsynaptic neurons [131], thereby enabling communication and the transmission of information.”
Hippocampal proteomic changes in high-fat diet-induced obese mice associated with memory decline
Lu, P., Gao, C.-X., Luo, F.-J., Huang, Y.-T., Gao, M., & Long, Y. (2023) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2023.109554 · Cited by 7 · see citing works
Comprehensive analysis of slow-fast denatured Morris-Lecar neurons
Ghosh, I., Fatoyinbo, H. O., & Muni, S. S. (2025) · Physical review. E · doi:10.1103/physreve.111.044204 · Cited by 7 · see citing works
Kaizuka, T., Hirouchi, T., Saneyoshi, T., Shirafuji, T., Collins, M. O., Grant, S. G. N., Hayashi, Y., & Takumi, T. (2024) · PLoS Biology · doi:10.1371/journal.pbio.3002006 · Cited by 12 · see citing works
Self-citationMelišková, V., Havránek, T., Bačová, Z., & Bakoš, J. (2021) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2004106 · Cited by 7 · see citing works
“synaptic scaffolding proteins at glutamatergic and gammaaminobutyric acid–(GABA)ergic–synapses, thereby suggesting their involvement in the etiology of neurodevelopmental disorders [10, 11].”
BackgroundMolecular Physiology of the Neuronal Synapse
Ramírez-Expósito, M. J., Cueto-Ureña, C., & Martínez-Martos, J. M. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48010088 · Cited by 6 · see citing works
“In the early 2000s, major advances occurred with the discovery that the synapse proteome is complex, comprising over a thousand conserved proteins, particularly within excitatory synapses [9].”
InfluentialRemodeling of the postsynaptic proteome in male mice and marmosets during synapse development
Kaizuka, T., Suzuki, T., Kishi, N., Tamada, K., Kilimann, M. W., Ueyama, T., Watanabe, M., Shimogori, T., Okano, H., Dohmae, N., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46529-9 · Cited by 9 · see citing works
“Proteome analysis of the PSD has been performed for various species under both physiological and pathological conditions 18 .”
BackgroundSelf-citationVilela, J. E. R., Martiniano, H., Marques, A. R., Santos, J. X., Asif, M., Rasga, C., Oliveira, G., & Vicente, A. M. (2023) · Biomedicines · doi:10.3390/biomedicines11112971 · Cited by 7 · see citing works
“…that genes encoding synaptic proteins, including synaptic adhesion molecules such as neuroligins, neurexins, cadherins and contactins, synaptic scaffold proteins, ion channels and neurotransmitter receptors are involved in ASD and in other neurodevelopmental and neurological disorders [22].”
BackgroundMinehart, J. A., & Speer, C. M. (2021) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2020.615059 · Cited by 8 · see citing works
Hrynchak, M. V., Rierola, M., Golovyashkina, N., Penazzi, L., Pump, W. C., David, B., Sündermann, F., Brandt, R., & Bakota, L. (2020) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2020.00016 · Cited by 7 · see citing works
Hsu, T.-T., Chen, C.-P., Lin, M.-H., Hung, T.-E., Huang, T., Wang, C.-Y., & Hsueh, Y. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03340-2 · Cited by 3 · see citing works
eSylites: Synthetic Probes for Visualization and Topographic Mapping of Single Excitatory Synapses
Huhn, C., Ho, S., Schulte, C., Khayenko, V., Hemmen, K., Peulen, T.-O., Wiessler, A.-L., Bothe, S., Bej, A., Talucci, I., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c00772 · Cited by 5 · see citing works
Development of Peptide-Based Probes for Molecular Imaging of the Postsynaptic Density in the Brain
Fernandes, E. F. A., Palner, M., Raval, N. R., Jeppesen, T. E., Danková, D., Bærentzen, S. L., Werner, C. D., Eilts, J., Maric, H. M., Doose, S., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00615 · Cited by 6 · see citing works
Li, D., Sun, N., Guo, Y., Huang, S., Yin, C., Xiao, Y., & Ma, W. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04136-1 · Cited by 5 · see citing works
“…induce global alterations in PSD composition, and according to literature, the size of the post-synaptic compartment, including the quantity of PSD-95, can autonomously influence the number of AMPARs [31], which may be one of the reasons for changes in psychological and cognitive characteristics.”
PSINDB: the postsynaptic protein–protein interaction database
Kálmán, Z. E., Dudola, D., Mészáros, B., Gáspári, Z., & Dobson, L. (2022) · Database · doi:10.1093/database/baac007 · Cited by 6 · see citing works
“Mutations in postsynaptic proteins are responsible for a wide range of neurological and psychiatric diseases (6), many of them likely to be heritable as suggested by a growing number of evidence, such as in the case of autism spectrum disorder (7, 8).”
Razar, R. B. B. A., Qu, Y., Gunaseelan, S., & Chua, J. J. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.327327 · Cited by 5 · see citing works
“Curiously, loss of FEZ1 in an adult hippocampal neurogenesis model reportedly induces over-proliferation of dendrites without impairing axon development (Kang et al., 2011).”
BackgroundMapping Functional Protein Neighborhoods in the Mouse BrainPreprint
Liebeskind, B. J., Young, R. L., Halling, D. B., Aldrich, R. W., & Marcotte, E. M. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.26.920447 · Cited by 5 · see citing works
“loci for autism spectrum disorder, like cell adhesion (Stewart, 2015), postsynaptic density (Kaizuka and Takumi, 2018), the cytoskeleton (Lasser et al.”
BackgroundDisentangling the role of tau pathology in autism spectrum disorders
Villavicencio-Tejo, F., Olesen, M. A., Moya, M. L., & Quintanilla, R. A. (2025) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111496 · Cited by 4 · see citing works
Altered odor perception in Dlgap2 mutant mice, a mouse model of autism spectrum disorder.
Chen, Y.-F., Tsao, C.-Y., Chen, Y.-T., Chang, H.-C., Li, W.-Y., Chiang, J., Chen, C.-F. F., Chen, C.-H., Gau, S., Lee, K.-Y., et al. (2024) · Behavioural Brain Research · doi:10.1016/j.bbr.2024.115365 · Cited by 4 · see citing works
Kim, S. R., Eom, Y., & Lee, S. H. (2023) · Neurochemistry International · doi:10.1016/j.neuint.2023.105570 · Cited by 6 · see citing works
Tyrtyshnaia, A. A., Manzhulo, O. S., & Manzhulo, I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241210014 · Cited by 5 · see citing works
“1) encodes a protein that is expressed in the postsynaptic density (PSD) and is inherently associated with the regulation of synaptic plasticity and hence memory consolidation processes [51].”
BackgroundKaizuka, T., Suzuki, T., Kishi, N., Kilimann, M. W., Ueyama, T., Watanabe, M., Okano, H., Dohmae, N., & Takumi, T. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.05.490828 · Cited by 4 · see citing works
Self-citationYim, K., Baumgartner, M., Krenzer, M., Larios, M. F. R., Hill-Terán, G., Nottoli, T., Muhle, R., & Noonan, J. P. (2025) · Cell Genomics · doi:10.1016/j.xgen.2025.100986 · Cited by 12 · see citing works
Time series analysis of coupled slow–fast neuron models: From Hurst exponent to Granger causality
Ghosh, I., Fatoyinbo, H. O., & Muni, S. S. (2025) · Chaos An Interdisciplinary Journal of Nonlinear Science · doi:10.1063/5.0291493 · Cited by 1 · see citing works
“…those consisting of asymmetric junctions alongside a dense protein complex associated with the postsynaptic membranes of the excitatory synapses [Kaizuka and Takumi, 2018], and negative coupling represents those consisting of symmetrical synaptic junctions alongside lacking the dense protein…”
Abdullah, A. H. A., Jufri, N., Masre, S. F., Rajab, N., Damanhuri, H., Roos, N. C. C., & Ibrahim, F. (2024) · Turkish Journal of Biochemistry · doi:10.1515/tjb-2024-0041 · Cited by 3 · see citing works
“SYN is a glycoprotein that is present in the membrane of neuron synaptic vesicles [40] and PSD95 is a protein complex that is attached to the postsynaptic membrane [41], so the decreased level of both proteins indicated that synapse signaling is a ff ected.”
Karatoprak, S., Açıkel, S., Akyildiz, A., Çoşkun, F., & Yerlikaya, F. (2022) · International Journal of Developmental Disabilities · doi:10.1080/20473869.2022.2137287 · Cited by 3 · see citing works
“Previous studies have also shown that the changes in cell adhesion molecules, scaffold proteins, receptors and cyto-skeletal proteins, which play a key role in synaptic transmission and plasticity, might be associated with many neurodevelopmental disorders, including ASD (Kaizuka and Takumi 2018).”
How copy number variations shape brain developmental disorders: Unraveling the synaptic puzzle
Wang, T., TRABZONLU, K., Jones, E. F., & Syed, Y. A. (2025) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.70009 · Cited by 2 · see citing works
“15 During embryonic development in mice, PSD maturation follows a sequential process: GKAP binds to PSD-95 fi rst, followed by SHANK protein incorporation, re fl ecting dynamic synaptogenesis.”
InfluentialMeringolo, M., Montanari, M., D’Antoni, S., Martella, G., Atiallah, I. E., Ponterio, G., Tassone, A., Reverte, I., Caprioli, D., Strimpakos, G., et al. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70253 · Cited by 3 · see citing works
“Overwhelming evidence correlates PSD-95 disruption to cognitive and learning deficits in ASD (Kaizuka and Takumi 2018).”
Vellucci, L., Simone, G. D., Morley-Fletcher, S., Buonaguro, E., Avagliano, C., Barone, A., Maccari, S., Iasevoli, F., & de Bartolomeis, A. (2024) · Progress in Neuro-psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.111032 · Cited by 2 · see citing works
“…Homer family proteins, Shank family proteins, and Postsynaptic density protein 95 - PSD-95) have been linked to neurodevelopmental disorders also emerging after perinatal stress exposure (Berdenis van Berlekom et al. 2020; Buonaguro et al. 2020; Kaizuka and Takumi 2018; Osimo et al. 2019).”
Mazuecos, L., Artigas-Jerónimo, S., Pintado, C., Gómez, O., Rubio, B., Arribas, C., Andrés, A., Villar, M., & Gallardo, N. (2024) · Life Science · doi:10.1016/j.lfs.2024.122649 · Cited by 2 · see citing works
“These proteins influence the sorting, trafficking, and delivery of synaptic components and organelles, thereby affecting synapse formation and maintenance in the adult hypothalamus [33,34].”
BackgroundSaoud, H., Kereselidze, E., Eybrard, S., & Louilot, A. (2021) · bioRxiv · doi:10.1101/2021.02.16.431488 · Cited by 2
Carbonell, A. U., Freire‐Cobo, C., Deyneko, I. V., Erdjument‐Bromage, H., Clipperton‐Allen, A. E., Rasmusson, R. L., Page, D. T., Neubert, T. A., & Jordan, B. A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.02.429412 · Cited by 2 · see citing works
Shah, K., & Zhang, Y. (2026) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2026.1831452 · Cited by 1 · see citing works
“Understanding the regulatory roles of CaM is gaining massive significance, as disruptions in the CaM signaling pathway have been associated with neurological disorders like Parkinson’s disease, Alzheimer’s, and Autism spectrum disorders (Kaizuka and Takumi, 2018).”
- Authors
- Kaizuka, T., & Takumi, T.
- Affiliations
- RIKEN Center for Brain Science (JP)
- Corresponding author
- Takumi, Toru
- Venue
- The Journal of Biochemistry
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-02-05
- Volume
- 163
- Issue
- 6
- Pages
- 447-455
- ISSN
- 0021-924X (ISSN-L)
- 1756-2651
- OpenAlex
- W2792126067
- Cited by
- 131
- References
- 0
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 24 · 2023: 12 · 2022: 22 · 2021: 19 · 2020: 14 · 2019: 10 · 2018: 3
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- JSPS
- Ministry of Education, Culture, Sports, Science and Technology
- Takeda Science Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- postsynaptic density, postsynaptic density proteins, neurodevelopmental disorders, autism spectrum disorder, schizophrenia, synaptic transmission, synaptic plasticity, excitatory synapses, neuropsychiatric disorders
- MeSH terms
- Animals, Humans, Nerve Tissue Proteins, Proteomics, Neurodevelopmental Disorders
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