{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:45:42Z","timestamp":1785422742535,"version":"3.56.0"},"reference-count":93,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82571563"],"award-info":[{"award-number":["82571563"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371381"],"award-info":[{"award-number":["82371381"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171363"],"award-info":[{"award-number":["82171363"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82571666"],"award-info":[{"award-number":["82571666"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171321"],"award-info":[{"award-number":["82171321"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82571563"],"award-info":[{"award-number":["82571563"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82371381"],"award-info":[{"award-number":["82371381"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82171363"],"award-info":[{"award-number":["82171363"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82571666"],"award-info":[{"award-number":["82571666"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82171321"],"award-info":[{"award-number":["82171321"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>SYNGAP1-related intellectual disability presents a therapeutic paradox where genetic rescue is highly effective in neonates but limited in adults, suggesting that deficiency represents a developmental trajectory violation rather than a static biochemical defect. By synthesizing molecular, biophysical, and clinical evidence, this review proposes the \u201cSynaptic Clock\u201d framework, redefining SynGAP1 as a critical developmental regulator. We hypothesize that SynGAP1 operates through a strictly ordered temporal sequence: Phase I (Scaffold Assembly) utilizes the \u03b11 isoform and phase separation to establish the structural postsynaptic density, while Phase II (Catalytic Refinement) involves isoform switching to enable activity-dependent plasticity and homeostatic scaling. This model characterizes synaptic maturation as a biophysical transition from a fluid scaffold to a consolidated gel, potentially marking the biological closure of structural rescue windows. Based on this hypothesized temporal mapping, we establish a phase-stratified therapeutic roadmap\u2014transitioning from early-stage \u201creset\u201d strategies like gene replacement to late-stage \u201crefinement\u201d and \u201ccompensation\u201d via pharmacological and neuromodulatory interventions. Ultimately, validating phase-specific biomarkers, including gamma oscillations and isoform stoichiometry, is essential for shifting from generic interventions toward precision, phase-matched medicine for neurodevelopmental timing.<\/jats:p>","DOI":"10.3390\/biom16060876","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:49:42Z","timestamp":1781743782000},"page":"876","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Synaptic Clock: SynGAP1 as a Molecular Timer of Postsynaptic Density Consolidation"],"prefix":"10.3390","volume":"16","author":[{"given":"Zixuan","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibin","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanjiang","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanwei","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"The Second Regiment, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0746-939X","authenticated-orcid":false,"given":"Peng","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/s41580-024-00802-3","article-title":"Circadian clock communication during homeostasis and ageing","volume":"26","author":"Mortimer","year":"2025","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/s13238-016-0366-2","article-title":"Physiological links of circadian clock and biological clock of aging","volume":"8","author":"Liu","year":"2017","journal-title":"Protein Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10392","DOI":"10.1038\/s41467-024-54694-0","article-title":"Synaptic connectome of the Drosophila circadian clock","volume":"15","author":"Reinhard","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7257","DOI":"10.1038\/s41467-024-51716-9","article-title":"Prefrontal cortex molecular clock modulates development of depression-like phenotype and rapid antidepressant response in mice","volume":"15","author":"Sarrazin","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41583-018-0088-y","article-title":"Rhythms of life: Circadian disruption and brain disorders across the lifespan","volume":"20","author":"Logan","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8862","DOI":"10.1523\/JNEUROSCI.3213-04.2004","article-title":"SynGAP regulates spine formation","volume":"24","author":"Vazquez","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/j.biopsych.2010.11.015","article-title":"De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism","volume":"69","author":"Hamdan","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s11689-018-9225-1","article-title":"The first international conference on SYNGAP1-related brain disorders: A stakeholder meeting of families, researchers, clinicians, and regulators","volume":"10","author":"Weldon","year":"2018","journal-title":"J. Neurodev. Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.pediatrneurol.2025.05.017","article-title":"SYNGAP1-Related Intellectual Disability: Meaningful Clinical Outcomes and Development of a Disease Concept Model Draft","volume":"169","author":"Cunnane","year":"2025","journal-title":"Pediatr. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.1111\/epi.18469","article-title":"Familial SYNGAP1 variants define the boundaries of a complex neurodevelopmental disorder with epilepsy","volume":"66","author":"Harrison","year":"2025","journal-title":"Epilepsia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"108500","DOI":"10.1016\/j.yebeh.2021.108500","article-title":"SYNGAP1-related developmental and epileptic encephalopathy: The impact on daily life","volume":"127","author":"Santangelo","year":"2022","journal-title":"Epilepsy Behav."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/humu.22248","article-title":"Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency","volume":"34","author":"Berryer","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.biopsych.2014.08.001","article-title":"Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly","volume":"77","author":"Aceti","year":"2015","journal-title":"Biol. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.cell.2012.08.045","article-title":"Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses","volume":"151","author":"Clement","year":"2012","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e46752","DOI":"10.7554\/eLife.46752","article-title":"Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior","volume":"8","author":"Creson","year":"2019","journal-title":"eLife"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1523\/JNEUROSCI.0420-19.2020","article-title":"Twenty Years of SynGAP Research: From Synapses to Cognition","volume":"40","author":"Gamache","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Greco, M.R., Chatterjee, M., Taylor, A.M., and Gropman, A.L. (2025). SYNGAP1 Syndrome and the Brain Gene Registry. Genes, 16.","DOI":"10.3390\/genes16040405"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/nrn2540","article-title":"Organization and dynamics of PDZ-domain-related supramodules in the postsynaptic density","volume":"10","author":"Feng","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Brill, J., Clarke, B., Hong, I., and Huganir, R.L. (2025). Dissociation of SYNGAP1 enzymatic and structural roles: Intrinsic excitability and seizure susceptibility. Proc. Natl. Acad. Sci. USA, 122, Correction in Proc. Natl. Acad. Sci. USA\u00a02025, 122, e2518853122.","DOI":"10.1073\/pnas.2427288122"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4344","DOI":"10.1073\/pnas.0600084103","article-title":"SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons","volume":"103","author":"Rumbaugh","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.tibs.2011.03.006","article-title":"The Ras-ERK and PI3K-mTOR pathways: Cross-talk and compensation","volume":"36","author":"Mendoza","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.1007\/s11064-022-03623-y","article-title":"Rho-Rho-Kinase Regulates Ras-ERK Signaling Through SynGAP1 for Dendritic Spine Morphology","volume":"47","author":"Wu","year":"2022","journal-title":"Neurochem. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1111\/ejn.15043","article-title":"SynGAP is expressed in the murine suprachiasmatic nucleus and regulates circadian-gated locomotor activity and light-entrainment capacity","volume":"53","author":"Aten","year":"2021","journal-title":"Eur. J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jeyabalan, N., and Clement, J.P. (2016). SYNGAP1: Mind the Gap. Front. Cell Neurosci., 10.","DOI":"10.3389\/fncel.2016.00032"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e70066","DOI":"10.1002\/mgg3.70066","article-title":"Novel De Novo Intronic Variant of SYNGAP1 Associated With the Neurodevelopmental Disorders","volume":"13","author":"Xie","year":"2025","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41583-024-00815-z","article-title":"A structural role for SynGAP","volume":"25","author":"Yates","year":"2024","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e56273","DOI":"10.7554\/eLife.56273","article-title":"SynGAP isoforms differentially regulate synaptic plasticity and dendritic development","volume":"9","author":"Araki","year":"2020","journal-title":"eLife"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"114733","DOI":"10.1016\/j.celrep.2024.114733","article-title":"Key roles of C2\/GAP domains in SYNGAP1-related pathophysiology","volume":"43","author":"Katsanevaki","year":"2024","journal-title":"Cell Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1038\/ncomms1900","article-title":"SynGAP isoforms exert opposing effects on synaptic strength","volume":"3","author":"McMahon","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11024","DOI":"10.1002\/chem.201905269","article-title":"Pressure Sensitivity of SynGAP\/PSD-95 Condensates as a Model for Postsynaptic Densities and Its Biophysical and Neurological Ramifications","volume":"26","author":"Cinar","year":"2020","journal-title":"Chemistry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e75707","DOI":"10.7554\/eLife.75707","article-title":"Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection","volume":"11","author":"Kilinc","year":"2022","journal-title":"eLife"},{"key":"ref_32","first-page":"296","article-title":"Anchoring high concentrations of SynGAP at postsynaptic densities via liquid-liquid phase separation","volume":"10","author":"Zeng","year":"2019","journal-title":"Small GTPases"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/j.cell.2016.07.008","article-title":"Phase Transition in Postsynaptic Densities Underlies Formation of Synaptic Complexes and Synaptic Plasticity","volume":"166","author":"Zeng","year":"2016","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e190","DOI":"10.1111\/j.1528-1167.2011.03304.x","article-title":"A balanced translocation disrupts SYNGAP1 in a patient with intellectual disability, speech impairment, and epilepsy with myoclonic absences (EMA)","volume":"52","author":"Klitten","year":"2011","journal-title":"Epilepsia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1242\/jcs.200295","article-title":"The wisdom of crowds: Regulating cell function through condensed states of living matter","volume":"130","author":"Alberti","year":"2017","journal-title":"J. Cell Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nrm.2017.7","article-title":"Biomolecular condensates: Organizers of cellular biochemistry","volume":"18","author":"Banani","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"eaaf4382","DOI":"10.1126\/science.aaf4382","article-title":"Liquid phase condensation in cell physiology and disease","volume":"357","author":"Shin","year":"2017","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/s41593-019-0579-9","article-title":"Phase separation at the synapse","volume":"23","author":"Chen","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"14823","DOI":"10.1074\/jbc.REV119.007895","article-title":"Formation of biological condensates via phase separation: Characteristics, analytical methods, and physiological implications","volume":"294","author":"Feng","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"100762","DOI":"10.1016\/j.mser.2023.100762","article-title":"Liquid-liquid phase separation (LLPS) in synthetic biosystems","volume":"157","author":"Kang","year":"2024","journal-title":"Mater. Sci. Eng. R Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1038\/s41557-022-00946-9","article-title":"O-GlcNAcylation modulates liquid-liquid phase separation of SynGAP\/PSD-95","volume":"14","author":"Lv","year":"2022","journal-title":"Nat. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.neuron.2014.12.023","article-title":"Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP","volume":"85","author":"Araki","year":"2015","journal-title":"Neuron"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.neuron.2004.08.003","article-title":"SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation","volume":"43","author":"Krapivinsky","year":"2004","journal-title":"Neuron"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ijdevneu.2019.08.003","article-title":"SYNGAP1 mutations: Clinical, genetic, and pathophysiological features","volume":"78","author":"Agarwal","year":"2019","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"15073","DOI":"10.1523\/JNEUROSCI.1087-15.2015","article-title":"Convergence of Hippocampal Pathophysiology in Syngap+\/\u2212 and Fmr1\u2212\/y Mice","volume":"35","author":"Barnes","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41398-023-02486-3","article-title":"AKT and MAPK signaling pathways in hippocampus reveals the pathogenesis of depression in four stress-induced models","volume":"13","author":"Li","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Omolekan, T.O., Chamcheu, J.C., Buerger, C., and Huang, S. (2024). PI3K\/AKT\/mTOR Signaling Network in Human Health and Diseases. Cells, 13.","DOI":"10.3390\/cells13171500"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e52656","DOI":"10.7554\/eLife.52656","article-title":"A sex difference in the response of the rodent postsynaptic density to synGAP haploinsufficiency","volume":"9","author":"Mastro","year":"2020","journal-title":"eLife"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4908","DOI":"10.1074\/jbc.M114.614420","article-title":"Phosphorylation of synaptic GTPase-activating protein (synGAP) by Ca2+\/calmodulin-dependent protein kinase II (CaMKII) and cyclin-dependent kinase 5 (CDK5) alters the ratio of its GAP activity toward Ras and Rap GTPases","volume":"290","author":"Walkup","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1097\/00001756-200502080-00016","article-title":"Enhanced Ras activity promotes spine formation in synRas mice neocortex","volume":"16","author":"GRtner","year":"2005","journal-title":"Neuroreport"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Cherra, S.J., and Lamb, R. (2024). Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease. Front. Mol. Neurosci., 17.","DOI":"10.3389\/fnmol.2024.1352731"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.str.2019.11.018","article-title":"Shank3 Binds to and Stabilizes the Active Form of Rap1 and HRas GTPases via Its NTD-ANK Tandem with Distinct Mechanisms","volume":"28","author":"Cai","year":"2020","journal-title":"Structure"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1038\/s44318-025-00390-8","article-title":"Different Ras isoforms regulate synaptic plasticity in opposite directions","volume":"44","author":"Jiang","year":"2025","journal-title":"EMBO J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.neuron.2018.03.049","article-title":"Ras and Rap Signal Bidirectional Synaptic Plasticity via Distinct Subcellular Microdomains","volume":"98","author":"Zhang","year":"2018","journal-title":"Neuron"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/S0092-8674(02)00897-8","article-title":"Ras and Rap control AMPA receptor trafficking during synaptic plasticity","volume":"110","author":"Zhu","year":"2002","journal-title":"Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"eadk1291","DOI":"10.1126\/science.adk1291","article-title":"SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity","volume":"383","author":"Araki","year":"2024","journal-title":"Science"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e2308891120","DOI":"10.1073\/pnas.2308891120","article-title":"Mouse models of SYNGAP1-related intellectual disability","volume":"120","author":"Araki","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1111\/jnc.14988","article-title":"SynGAP splice variants display heterogeneous spatio-temporal expression and subcellular distribution in the developing mammalian brain","volume":"154","author":"Gou","year":"2020","journal-title":"J. Neurochem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"7980","DOI":"10.1523\/JNEUROSCI.1367-20.2020","article-title":"SYNGAP1 Controls the Maturation of Dendrites, Synaptic Function, and Network Activity in Developing Human Neurons","volume":"40","author":"Llamosas","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3058","DOI":"10.1016\/j.neuron.2024.07.007","article-title":"SYNGAP1 deficiency disrupts synaptic neoteny in xenotransplanted human cortical neurons in vivo","volume":"112","author":"Vermaercke","year":"2024","journal-title":"Neuron"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Zhang, J., Xue, G., Wang, X., Rao, X., Chen, J., Fan, L., Liu, L., and Gan, J. (2026). Research progress in SYNGAP1-related neurodevelopmental disorders: From pathogenesis to therapeutic strategies. Front. Neurol., 17.","DOI":"10.3389\/fneur.2026.1773363"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1038\/s41593-023-01477-3","article-title":"Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis","volume":"26","author":"Birtele","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"11060","DOI":"10.1038\/s41467-025-66069-0","article-title":"Syngap1 and the development of murine neocortical progenitor cells","volume":"16","author":"Barao","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1021\/acs.jpcb.2c00794","article-title":"Effects of Cosolvents and Crowding Agents on the Stability and Phase Transition Kinetics of the SynGAP\/PSD-95 Condensate Model of Postsynaptic Densities","volume":"126","author":"Cinar","year":"2022","journal-title":"J. Phys. Chem. B"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/s41598-018-20610-y","article-title":"Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability","volume":"8","author":"Coba","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1016\/j.neuron.2014.05.015","article-title":"Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons","volume":"82","author":"Ozkan","year":"2014","journal-title":"Neuron"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"13673","DOI":"10.1523\/JNEUROSCI.4695-08.2008","article-title":"SynGAP regulates steady-state and activity-dependent phosphorylation of cofilin","volume":"28","author":"Carlisle","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6398","DOI":"10.1016\/j.ymthe.2025.09.040","article-title":"AAV delivery of full-length SYNGAP1 rescues epileptic and behavioral phenotypes in a mouse model of SYNGAP1-related disorders","volume":"33","author":"Quinlan","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1038\/npp.2008.223","article-title":"Reduced expression of the NMDA receptor-interacting protein SynGAP causes behavioral abnormalities that model symptoms of Schizophrenia","volume":"34","author":"Guo","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/npr2.12073","article-title":"Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice","volume":"39","author":"Nakajima","year":"2019","journal-title":"Neuropsychopharmacol. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1038\/s41467-023-38273-3","article-title":"Mapping PTBP2 binding in human brain identifies SYNGAP1 as a target for therapeutic splice switching","volume":"14","author":"Felix","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_72","first-page":"101576","article-title":"Accelerating therapeutic development and clinical trial readiness for STXBP1 and SYNGAP1 disorders","volume":"54","author":"Marotta","year":"2024","journal-title":"Curr. Probl. Pediatr. Adolesc. Health Care"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1016\/j.neuron.2023.02.021","article-title":"Upregulation of SYNGAP1 expression in mice and human neurons by redirecting alternative splicing","volume":"111","author":"Yang","year":"2023","journal-title":"Neuron"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s00221-021-06254-x","article-title":"Pharmacological intervention in young adolescents rescues synaptic physiology and behavioural deficits in Syngap1+\/\u2212 mice","volume":"240","author":"Verma","year":"2022","journal-title":"Exp. Brain Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.pharep.2018.02.021","article-title":"Chronic treatment with a MEK inhibitor reverses enhanced excitatory field potentials in mice","volume":"70","author":"Kopanitsa","year":"2018","journal-title":"Pharmacol. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4157","DOI":"10.1038\/s41467-023-39894-4","article-title":"Membranes prime the RapGEF EPAC1 to transduce cAMP signaling","volume":"14","author":"Sartre","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e14408","DOI":"10.1111\/acel.14408","article-title":"Epigenetic modulation rescues neurodevelopmental deficits in mice","volume":"24","author":"Singh","year":"2025","journal-title":"Aging Cell"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Foldi, T., Lorincz, M.L., and Berenyi, A. (2021). Temporally Targeted Interactions With Pathologic Oscillations as Therapeutical Targets in Epilepsy and Beyond. Front. Neural Circuits, 15.","DOI":"10.3389\/fncir.2021.784085"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Krawinkel, L.A., Engel, A.K., and Hummel, F.C. (2015). Modulating pathological oscillations by rhythmic non-invasive brain stimulation-a therapeutic concept?. Front. Syst. Neurosci., 9.","DOI":"10.3389\/fnsys.2015.00033"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.seizure.2024.03.001","article-title":"Neurostimulation targeting the epileptic focus: Current understanding and perspectives for treatment","volume":"117","author":"Nitsche","year":"2024","journal-title":"Seizure"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Takeuchi, Y., Li, Q., Kawano, T., Nagai, J., and Mima, T. (2022). Editorial: Oscillotherapeutics-toward real-time control of pathological oscillations in the brain. Front. Behav. Neurosci., 16.","DOI":"10.3389\/fnbeh.2022.1021616"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41593-018-0268-0","article-title":"SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits","volume":"21","author":"Michaelson","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"RP97100","DOI":"10.7554\/eLife.97100.4","article-title":"Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex","volume":"13","author":"Francavilla","year":"2025","journal-title":"eLife"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.biopsych.2019.12.025","article-title":"Low-Dose Perampanel Rescues Cortical Gamma Dysregulation Associated With Parvalbumin Interneuron GluA2 Upregulation in Epileptic Mice","volume":"87","author":"Sullivan","year":"2020","journal-title":"Biol. Psychiatry"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"fcac263","DOI":"10.1093\/braincomms\/fcac263","article-title":"Abnormal brain state distribution and network connectivity in a SYNGAP1 rat model","volume":"4","author":"Lu","year":"2022","journal-title":"Brain Commun."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Chakraborty, S., Parayil, R., Mishra, S., Nongthomba, U., and Clement, J.P. (2022). Epilepsy Characteristics in Neurodevelopmental Disorders: Research from Patient Cohorts and Animal Models Focusing on Autism Spectrum Disorder. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810807"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e214148","DOI":"10.1212\/WNL.0000000000214148","article-title":"Quantitative EEG Biomarkers in the Genetic Epilepsies and Associations With Neurologic Outcomes","volume":"105","author":"Galer","year":"2025","journal-title":"Neurology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1055\/s-0035-1554098","article-title":"SYNGAP1 Mutation in Focal and Generalized Epilepsy: A Literature Overview and A Case Report with Special Aspects of the EEG","volume":"46","author":"Funke","year":"2015","journal-title":"Neuropediatrics"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"110122","DOI":"10.1016\/j.pnpbp.2020.110122","article-title":"Prenatal disruption of D1R-SynGAP complex causes cognitive deficits in adulthood","volume":"105","author":"Lai","year":"2021","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_90","first-page":"23146","article-title":"pSynGAP1 disturbance-mediated hippocampal oscillation network impairment might contribute to long-term neurobehavioral abnormities in sepsis survivors","volume":"12","author":"Wang","year":"2020","journal-title":"Aging"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"102137","DOI":"10.1016\/j.ctrv.2020.102137","article-title":"MEK inhibitor resistance mechanisms and recent developments in combination trials","volume":"92","author":"Kun","year":"2021","journal-title":"Cancer Treat. Rev."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Huo, X.L., Min, J.J., Pan, C.Y., Zhao, C.C., Pan, L.L., Gui, F.F., Jin, L., and Wang, X.T. (2014). Efficacy of lovastatin on learning and memory deficits caused by chronic intermittent hypoxia-hypercapnia: Through regulation of NR2B-containing NMDA receptor-ERK pathway. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0094278"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"111098","DOI":"10.1016\/j.yebeh.2026.111098","article-title":"SYNGAP1-related disorder: Pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches","volume":"182","author":"Samanta","year":"2026","journal-title":"Epilepsy Behav."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/6\/876\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T01:16:14Z","timestamp":1781745374000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/6\/876"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,15]]},"references-count":93,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["biom16060876"],"URL":"https:\/\/doi.org\/10.3390\/biom16060876","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,15]]}}}