{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T05:01:52Z","timestamp":1789794112558,"version":"4.0.1"},"reference-count":28,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CHEO RI","award":["5781"],"award-info":[{"award-number":["5781"]}]},{"name":"CHEO Foundation"},{"id":[{"id":"https:\/\/ror.org\/05qwhm044","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>DLG4-related synaptopathy (SHINE syndrome) is a rare neurodevelopmental disorder caused by pathogenic variants in DLG4, which encodes the postsynaptic scaffolding protein (PSD)-95, a central organizer of excitatory synapses. However, the cellular and network-level consequences of DLG4 haploinsufficiency in human neurons remain incompletely understood, and disease-targeted therapeutic strategies are lacking. Here, we used human induced neurons derived from an individual with SHINE syndrome to investigate the effects of PSD-95 deficiency on synaptic protein expression, neuronal morphology, and neuronal network activity. SHINE neurons exhibited reduced PSD-95 levels, impaired neurite morphology, reduced firing rate and burst frequency, prolonged burst duration, and reduced network synchrony. Treatment with the omega-3 (\u03c9-3) polyunsaturated fatty acid docosahexaenoic acid (DHA) significantly increased PSD-95 protein levels and improved multiple parameters of neuronal network activity. DHA exposure was also associated with trends toward increased extracellular signal-regulated kinase and cAMP response element-binding protein phosphorylation. Together, these findings show that patient-derived SHINE neurons exhibit altered postsynaptic organization, neuronal morphology, and network function and provide evidence that DHA may partially restore synaptic and network function in this disorder.<\/jats:p>","DOI":"10.3390\/cells15181688","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:41:35Z","timestamp":1789645295000},"page":"1688","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human Neuronal Modeling of DLG4-Related Synaptopathy Reveals Network Dysfunction and Partial Rescue by Omega-3 Fatty Acid Docosahexaenoic Acid (DHA)"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2687-7022","authenticated-orcid":false,"given":"Gerardo","family":"Medina","sequence":"first","affiliation":[{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1,  Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Lilia A.","family":"Rodriguez-Alcocer","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1,  Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Baird","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1,  Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Alex E.","family":"MacKenzie","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1,  Canada"},{"name":"Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada"},{"name":"Eric Poulin Center for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6329","DOI":"10.1523\/JNEUROSCI.5968-10.2011","article-title":"PSD-95 is required to sustain the molecular organization of the postsynaptic density","volume":"31","author":"Chen","year":"2011","journal-title":"J. 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