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Synaptic dysfunctions, including deficits in synaptogenesis, neurotransmission and plasticity, underlie various neurological diseases. Repressor element\u20101 silencing transcription factor (REST), an epigenetic transcription factor, plays a crucial role in neurodevelopment and neuroprotection by fine\u2010tuning the expression of neuronal genes. REST binds to the RE\u20101 motif on target genes and recruits cofactors to exert transcriptional regulation. Dysregulation of REST, affecting thousands of downstream neuronal genes, is characteristic of neurological diseases with synaptic dysfunctions, including Huntington's disease, Alzheimer's disease, epilepsy, cerebral ischaemia, bipolar disorder and Kleefstra syndrome. Research on REST\u2010targeted synaptic genes has been ongoing since 1993, using various fundamental and disease neuronal models. However, there has been no comprehensive review to consolidate the scattered knowledge of the regulatory role of REST in the synaptic system. Therefore, we reviewed and identified a list of REST\u2010targeted and \u2010regulated synaptic genes to address this gap. We found that REST plays significant roles in synapse development and function, particularly in the synaptic vesicle cycle, chemical neurotransmission systems and homeostasis of synaptic plasticity. Importantly, approaches to restore REST level in various neurological diseases have successfully rescued REST\u2010targeted synaptic gene expression and ameliorated their synaptic and neuronal functions. This review serves as a foundation for future research on REST and neurological diseases. It aims to delineate the regulatory role of REST in the synaptic system and explore the potential of targeting REST restoration to improve synaptic functions in various neurological conditions.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70132-fig-0006-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70132","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T03:55:20Z","timestamp":1750305320000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Regulatory Roles of\n                    <scp>REST<\/scp>\n                    in the Synaptic Development, Function and Related Neurological Disorders"],"prefix":"10.1111","volume":"169","author":[{"given":"Chong Teik","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medicine and Health Sciences Universiti Putra Malaysia  Serdang Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng Wei","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Faculty of Medicine and Health Sciences Universiti Putra Malaysia  Serdang Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medicine and Health Sciences Universiti Putra Malaysia  Serdang Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elysha 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