Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment

Filiz Çetinkaya; Duygu Bandırmalı; Güvem Gümüş Akay

doi:10.65092/autfm.1715662

TR EN

Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment

Abstract

The human brain is comprised of intricate neuronal networks that comprise approximately 100 trillion synapses, which underpin functional connectivity. Disruptions in these synaptic connections play a fundamental role in several neurological disorders, such as autism spectrum disorder (ASD). During early development, genes related to ASD, coupled with environmental stressors, effect brain development and neural circuit formation. Genes associated with the structure and functioning of synapses demonstrate a significant prevalence of mutations within individuals diagnosed with ASD. In addition, environmental factors and mitochondrial dysfunction affecting synaptic metabolism also contribute to the pathophysiology of ASD. Understanding the link between synaptic dysfunction and autism symptoms may provide new perspectives for therapeutic approaches. The purpose of the present analysis is to furnish the reader with an overview of the findings pertaining to synaptic dysfunction in ASD.

Keywords

Autism spectrum disorder, Synaptic transmission, Synapse

Supporting Institution

This study received no financial support.

Thanks

We would like to thank and apologize to those scientists whose works have not been cited in this article due to limited space.

References

American Psychiatric Association D. Diagnostic and statistical manual of mental disorders: DSM-5: American psychiatric association Washington, DC; 2013.
Leblond CS, Le TL, Malesys S, et al. Operative list of genes associated with autism and neurodevelopmental disorders based on database review. Mol Cell Neurosci. 2021;113:103623.
Strathearn L, Momany A, Kovács EH, et al. The intersection of genome, epigenome and social experience in autism spectrum disorder: Exploring modifiable pathways for intervention. Neurobiol Learn Mem. 2023;202:107761.
Courchesne E, Pramparo T, Gazestani VH, et al. The ASD Living Biology: from cell proliferation to clinical phenotype. Mol Psychiatry. 2019;24(1):88-107.
Bourgeron T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci. 2015;16(9):551-63.
Qi C, Luo L-D, Feng I, et al. Molecular mechanisms of synaptogenesis. Front Synaptic Neurosci. 2022;14:939793.
Zhang Y, Tang R, Hu Z-M, et al. Key Synaptic Pathology in Autism Spectrum Disorder: Genetic Mechanisms and Recent Advances. J Integr Neurosci. 2024;23(10):184.
Baig DN, Yanagawa T, Tabuchi K. Distortion of the normal function of synaptic cell adhesion molecules by genetic variants as a risk for autism spectrum disorders. Brain Res Bull. 2017;129:82-90.
Chaste P, Klei L, Sanders SJ, et al. Adjusting head circumference for covariates in autism: clinical correlates of a highly heritable continuous trait. Biol Psychiatry. 2013;74(8):576-84.
Hahamy A, Behrmann M, Malach R. The idiosyncratic brain: distortion of spontaneous connectivity patterns in autism spectrum disorder. Nat Neurosci. 2015;18(2):302-9.

Masini E, Loi E, Vega-Benedetti AF, et al. An overview of the main genetic, epigenetic and environmental factors involved in autism spectrum disorder focusing on synaptic activity. Int J Mol Sci. 2020;21(21):8290.
de la Torre-Ubieta L, Won H, Stein JL, et al. Advancing the understanding of autism disease mechanisms through genetics. Nat Med. 2016;22(4):345-61.
Hayano Y, Miyoshi G, Paul A, et al. Cellular and molecular mechanisms that govern assembly, plasticity, and function of GABAergic inhibitory circuits in the mammalian brain. Front Cell Neurosci. 2025. p. 1568845.
Südhof TC, Malenka RC. Understanding synapses: past, present, and future. Neuron. 2008;60(3):469-76.
Kasem E, Kurihara T, Tabuchi K. Neurexins and neuropsychiatric disorders. Neurosci Res. 2018;127:53-60.
Südhof TC. Synaptic neurexin complexes: a molecular code for the logic of neural circuits. Cell. 2017;171(4):745-69.
Guang S, Pang N, Deng X, et al. Synaptopathology Involved in Autism Spectrum Disorder. Front Cell Neurosci. 2018;12:470.
Nguyen TA, Wu K, Pandey S, et al. A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y. Neuron. 2020;106(5):759-68.e7.
Blundell J, Blaiss CA, Etherton MR, et al. Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J Neurosci. 2010;30(6):2115-29.
Chen J, Yu S, Fu Y, et al. Synaptic proteins and receptors defects in autism spectrum disorders. Front Cell Neurosci. 2014;8:276.
Varghese M, Keshav N, Jacot-Descombes S, et al. Autism spectrum disorder: neuropathology and animal models. Acta Neuropathol. 2017;134:537-66.
Peñagarikano O, Abrahams BS, Herman EI, et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell. 2011;147(1):235-46.
Gerik‐Celebi HB, Bolat H, Unsel‐Bolat G. Rare heterozygous genetic variants of NRXN and NLGN gene families involved in synaptic function and their association with neurodevelopmental disorders. Dev Neurobiol. 2024; 84(3):158-168.
Agarwala S, Ramachandra NB. Role of CNTNAP2 in autism manifestation outlines the regulation of signaling between neurons at the synapse. Egyptian J Med Hum Genet. 2021;22:1-13.
Carroll L, Braeutigam S, Dawes JM, et al. Autism spectrum disorders: multiple routes to, and multiple consequences of, abnormal synaptic function and connectivity. Neuroscientist. 2021;27(1):10-29.
Mohapatra AN, Jabarin R, Ray N, et al. Impaired emotion recognition in Cntnap2-deficient mice is associated with hyper-synchronous prefrontal cortex neuronal activity. Mol Psychiatry. 2024:1-13.
Coley AA, Gao W-J. PSD95: A synaptic protein implicated in schizophrenia or autism? Prog Neuropsychopharmacol Biol Psychiatry. 2018;82:187-94.
Ball NJ, Barnett SF, Goult BT. Mechanically operated signalling scaffolds. Biochem Soc Trans. 2024;52(2):517-27.
Verpelli C, Schmeisser MJ, Sala C, et al. Scaffold proteins at the postsynaptic density. Adv Exp Med Biol. 2012:970:29-61.
Oliva C, Escobedo P, Astorga C, et al. Role of the MAGUK protein family in synapse formation and function. Dev Neurobiol. 2012;72(1):57-72.
Farahani M, Rezaei-Tavirani M, Zali A, et al. Systematic Analysis of Protein– Protein and Gene–Environment Interactions to Decipher the Cognitive Mechanisms of Autism Spectrum Disorder. Cell Mol Neurobiol. 2022;42(4):1091-103.
Fatemi SH, Eschenlauer A, Aman J, et al. Quantitative proteomics of dorsolateral prefrontal cortex reveals an early pattern of synaptic dysmaturation in children with idiopathic autism. Cereb Cortex. 2024;34(13):161-71.
Zhang S, Zhou Y, Shen J, et al. Early-Life Exposure to 4-Hydroxy-4′-Isopropoxydiphenylsulfone Induces Behavioral Deficits Associated with Autism Spectrum Disorders in Mice. Environ Sci Technol. 2024;58(36):15984-96.
Medina G, MacKenzie AE. Neurodevelopmental disorders and the role of PSD-95: Understanding pathways and pharmacological interventions. Adv Neurol. 2024;3(1):2095.
Shiraishi-Yamaguchi Y, Furuichi T. The Homer family proteins. Genome Biol. 2007;8:1-12.
Banerjee A, Luong JA, Ho A, et al. Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism- like social impairment. Mol Autism. 2016;7:1-15.
Lin R, Learman LN, Bangash MA, et al. Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome. Cell Rep. 2021;37(7). 110014.
Leblond CS, Nava C, Polge A, et al. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. PLoS Genet. 2014;10(9):e1004580.
Peca J, Feliciano C, Ting JT, et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. 2011;472(7344):437-42.
Howard MA, Elias GM, Elias LA, et al. The role of SAP97 in synaptic glutamate receptor dynamics. Proc Natl Acad Sci. 2010;107(8):3805-10.
Soler J, Fañanás L, Parellada M, et al. Genetic variability in scaffolding proteins and risk for schizophrenia and autism-spectrum disorders: a systematic review. J Psychiatry Neurosci. 2018;43(4):223-44.
Montgomery J, Zamorano P, Garner C. MAGUKs in synapse assembly and function: an emerging view. Cell Mol Life Sci. 2004;61:911-29.
Iossifov I, O’roak BJ, Sanders SJ, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515(7526):216-21.
Yoo T, Joshi S, Prajapati S, et al. A deficiency of the psychiatric risk gene DLG2/PSD-93 causes excitatory synaptic deficits in the dorsolateral striatum. Front Mol Neurosci. 2022;15:938590.
Jurado O, José MV, Frixione E. Fragile X mental retardation protein modulates translation of proteins with predicted tendencies for liquid-liquid phase separation. BioSystems. 2025:105405.
Saldarriaga W, Payán-Gómez C, González-Teshima LY, et al. Double genetic hit: fragile X syndrome and partial deletion of protein patched homolog 1 antisense as cause of severe autism spectrum disorder. J Dev Behav Pediatr. 2020;41(9):724-8.
Carlson GC. Glutamate receptor dysfunction and drug targets across models of autism spectrum disorders. Pharmacol Biochem Behav. 2012;100(4):850-4.
Bagni C, Tassone F, Neri G, et al. Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest. 2012;122(12):4314-22.
Eser M, Hekimoglu G, Kutlubay B, et al. Analysis of TSC1 and TSC2 genes and evaluation of phenotypic correlations with tuberous sclerosis. Mol Genet Genomics. 2025;300(1):1-10.
Karalis V, Wood D, Teaney NA, et al. The role of TSC1 and TSC2 proteins in neuronal axons. Mol Psychiatry. 2024:1-14.
Yehia L, Keel E, Eng C. The clinical spectrum of PTEN mutations. Annu Rev Med. 2020;71(1):103-16.
Rademacher S, Preußner M, Rehm MC, et al. PTEN controls alternative splicing of autism spectrum disorder-associated transcripts in primary neurons. Brain. 2025;148(1):47-54.
Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet. 2004;41(5):323-6.
Hashem S, Nisar S, Bhat AA, et al. Genetics of structural and functional brain changes in autism spectrum disorder. Transl Psychiatry. 2020;10(1):229.
Sarn N, Jaini R, Thacker S, et al. Cytoplasmic-predominant Pten increases microglial activation and synaptic pruning in a murine model with autism-like phenotype. Mol Psychiatry. 2021;26(5):1458-71.
Smith IN, Thacker S, Jaini R, et al. Dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes. J Biomol Struct Dyn. 2019;37(7):1766-82.
Moore JR. Regulation of Neuronal Cell-Type-Specific Transcription by Non- CG Methylation and MeCP2: Washington University in St. Louis; 2024.
Voineagu I, Wang X, Johnston P, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011;474(7351):380-4.
Maezawa I, Swanberg S, Harvey D, et al. Rett syndrome astrocytes are abnormal and spread MeCP2 deficiency through gap junctions. J Neurosci. 2009;29(16):5051-61.
Ballas N, Lioy DT, Grunseich C, et al. Non–cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nat Neurosci. 2009;12(3):311-7.
Lioy DT, Garg SK, Monaghan CE, et al. A role for glia in the progression of Rett’s syndrome. Nature. 2011;475(7357):497-500.
Peters SU, Hundley RJ, Wilson AK, et al. The behavioral phenotype in MECP 2 duplication syndrome: a comparison with idiopathic autism. Autism Res. 2013;6(1):42-50.
Wen Z, Cheng T-L, Li G-z, et al. Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation. Mol Autism. 2017;8:1-10.
Bonati MT, Russo S, Finelli P, et al. Evaluation of autism traits in Angelman syndrome: a resource to unfold autism genes. Neurogenetics. 2007;8:169-78.
Vatsa N, Jana NR. UBE3A and its link with autism. Frontiers in molecular neuroscience. 2018;11:448.
Kelleher RJ, Bear MF. The autistic neuron: troubled translation? Cell. 2008;135(3):401-6.
Vorstman J, Staal W, Van Daalen E, et al. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry. 2006;11(1):18-28.
Bolton PF, Dennis N, Browne C, et al. The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. Am J Med Genet. 2001;105(8):675-85.
Khatri N, Man H-Y. The autism and Angelman syndrome protein Ube3A/ E6AP: The gene, E3 ligase ubiquitination targets and neurobiological functions. Front Mol Neurosci. 2019;12:109.
Khaliulin I, Hamoudi W, Amal H. The multifaceted role of mitochondria in autism spectrum disorder. Mol Psychiatry. 2024:1-22.
Lindberg D, Shan D, Ayers-Ringler J, et al. Purinergic signaling and energy homeostasis in psychiatric disorders. Curr Mol Med. 2015;15(3):275-95.
Dhillon S, A Hellings J, G Butler M. Genetics and mitochondrial abnormalities in autism spectrum disorders: a review. Curr Genomics. 2011;12(5):322-32.
Valenti D, de Bari L, De Filippis B, et al. Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: an overview of Down syndrome, autism, Fragile X and Rett syndrome. Neurosci Biobehav Rev. 2014;46:202-17.
Vannelli A, Mariano V, Bagni C, et al. Activation of the 5-HT1A Receptor by Eltoprazine Restores Mitochondrial and Motor Deficits in a Drosophila Model of Fragile X Syndrome. Int J Mol Sci. 2024;25(16):8787.
Samanta S, Akhter F, Xue R, et al. Synaptic mitochondria glycation contributes to mitochondrial stress and cognitive dysfunction. Brain. 2025;148(1):262-75.
Frye RE, McCarty PJ, Werner BA, et al. Bioenergetic signatures of neurodevelopmental regression. Front Physiol. 2024;15:1306038.
Canitano R, Palumbi R. Excitation/inhibition modulators in autism spectrum disorder: current clinical research. Front Neurosci. 2021;15:753274.
Depienne C, Moreno-De-Luca D, Heron D, et al. Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders. Biol Psychiatry. 2009;66(4):349-59.
Martin ER, Menold M, Wolpert C, et al. Analysis of linkage disequilibrium in γ‐aminobutyric acid receptor subunit genes in autistic disorder. Am J Med Genet. 2000;96(1):43-8.
Nakatani J, Tamada K, Hatanaka F, et al. Abnormal behavior in a chromosome- engineered mouse model for human 15q11-13 duplication seen in autism. Cell. 2009;137(7):1235-46.
Fatemi SH, Halt AR, Stary JM, et al. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry. 2002;52(8):805-10.
Fatemi SH, Folsom TD, Reutiman TJ, et al. Expression of GABA B receptors is altered in brains of subjects with autism. Cerebellum. 2009;8:64-9.
Lodge D. The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclature. Neuropharmacology. 2009;56(1):6-21.
Purcell A, Jeon O, Zimmerman A, et al. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology. 2001;57(9):1618-28.
Rojas DC. The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. J Neural Transm. 2014;121:891-905.
Valbuena S, Lerma J. Kainate receptors, homeostatic gatekeepers of synaptic plasticity. Neuroscience. 2021;456:17-26.
Nisar S, Bhat AA, Masoodi T, et al. Genetics of glutamate and its receptors in autism spectrum disorder. Mol Psychiatry. 2022;27(5):2380-92.
Fatemi SH, Folsom TD, Kneeland RE, et al. Metabotropic glutamate receptor 5 upregulation in children with autism is associated with underexpression of both Fragile X mental retardation protein and GABAA receptor beta 3 in adults with autism. Anat Rec. 2011;294(10):1635-45.
Xu J, Zhu Y, Contractor A, et al. mGluR5 has a critical role in inhibitory learning. J Neurosci. 2009;29(12):3676-84.
Fard YA, Sadeghi EN, Pajoohesh Z, et al. Epigenetic underpinnings of the autistic mind: Histone modifications and prefrontal excitation/inhibition imbalance. Am J Med Genet B Neuropsychiatr Genet. 2024:e32986.
Vakilzadeh G, Maseko BC, Bartely TD, et al. Increased number of excitatory synapsis and decreased number of inhibitory synapsis in the prefrontal cortex in autism. Cereb Cortex. 2024;34(13):121-8.
Marshall AH, Boyle DJ, Hanson MA, et al. Arid1b haploinsufficiency in cortical inhibitory interneurons causes cell-type-dependent changes in cellular and synaptic development. bioRxiv. 2024:2024.06. 07.597984.
Meng J, Zhang L, Zhang Y-w. Microglial Dysfunction in Autism Spectrum Disorder. Neuroscientist. 2024;30(6):744-758.
Godavarthi SK, Li H-q, Pratelli M, et al. Embryonic exposure to environmental factors drives transmitter switching in the neonatal mouse cortex causing autistic-like adult behavior. Proc Natl Acad Sci USA. 2024;121(35):e2406928121.
Jimenez-Gomez A, Nguyen MX, Gill JS. Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction. Front Psychiatry. 2024;15:1304300.
Kerna NA, Ngwu DC, Keke CO, et al. The Gut-Brain Axis in Neurodevelopmental Disorders: Mechanistic Insights, Clinical Implications, and Public Health Strategies. Eur J Theor Appl Sci. 2024;2(6):580-96.
Pizzella A, Penna E, Liu Y, et al. Alterations of synaptic plasticity in Angelman syndrome model mice are rescued by 5-HT7R stimulation. Prog Neurobiol. 2024;242:102684.

Details

Primary Language

English

Subjects

Child and Adolescent Psychiatry, Neurosciences (Other)

Journal Section

Review

Authors

Filiz Çetinkaya
0000-0003-2587-7290
Türkiye

Duygu Bandırmalı
0000-0002-2724-4078
Türkiye

Güvem Gümüş Akay ^*
0000-0002-6564-3133
Türkiye

Publication Date

September 30, 2025

Submission Date

June 10, 2025

Acceptance Date

July 23, 2025

Published in Issue

Year 2025 Volume: 78 Number: 3

DOI

https://doi.org/10.65092/autfm.1715662

IZ

https://izlik.org/JA89UF52SS

APA

Çetinkaya, F., Bandırmalı, D., & Gümüş Akay, G. (2025). Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment. Ankara Üniversitesi Tıp Fakültesi Mecmuası, 78(3), 259-272. https://doi.org/10.65092/autfm.1715662

AMA

1.Çetinkaya F, Bandırmalı D, Gümüş Akay G. Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment. Ankara Üniversitesi Tıp Fakültesi Mecmuası. 2025;78(3):259-272. doi:10.65092/autfm.1715662

Chicago

Çetinkaya, Filiz, Duygu Bandırmalı, and Güvem Gümüş Akay. 2025. “Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment”. Ankara Üniversitesi Tıp Fakültesi Mecmuası 78 (3): 259-72. https://doi.org/10.65092/autfm.1715662.

EndNote

Çetinkaya F, Bandırmalı D, Gümüş Akay G (September 1, 2025) Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment. Ankara Üniversitesi Tıp Fakültesi Mecmuası 78 3 259–272.

IEEE

[1]F. Çetinkaya, D. Bandırmalı, and G. Gümüş Akay, “Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment”, Ankara Üniversitesi Tıp Fakültesi Mecmuası, vol. 78, no. 3, pp. 259–272, Sept. 2025, doi: 10.65092/autfm.1715662.

ISNAD

Çetinkaya, Filiz - Bandırmalı, Duygu - Gümüş Akay, Güvem. “Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment”. Ankara Üniversitesi Tıp Fakültesi Mecmuası 78/3 (September 1, 2025): 259-272. https://doi.org/10.65092/autfm.1715662.

JAMA

1.Çetinkaya F, Bandırmalı D, Gümüş Akay G. Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment. Ankara Üniversitesi Tıp Fakültesi Mecmuası. 2025;78:259–272.

MLA

Çetinkaya, Filiz, et al. “Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment”. Ankara Üniversitesi Tıp Fakültesi Mecmuası, vol. 78, no. 3, Sept. 2025, pp. 259-72, doi:10.65092/autfm.1715662.

Vancouver

1.Filiz Çetinkaya, Duygu Bandırmalı, Güvem Gümüş Akay. Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment. Ankara Üniversitesi Tıp Fakültesi Mecmuası. 2025 Sep. 1;78(3):259-72. doi:10.65092/autfm.1715662

Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment

Otizmin Şifresini Çözmek: Nörogelişimde Sinaptik Disfonksiyonun Rolü

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Keywords

Decoding Autism: The Role of Synaptic Dysfunction in Neurodevelopment

Abstract

Keywords

Supporting Institution

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Acceptance Date

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