Human Neuronal Modeling of DLG4-Related Synaptopathy Reveals Network Dysfunction and Partial Rescue by Omega-3 Fatty Acid Docosahexaenoic Acid (DHA)

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 (ω-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.