Human Neuronal Modeling of DLG4-Related Synaptopathy Reveals Network Dysfunction and Partial Rescue by Omega-3 Fatty Acid Docosahexaenoic Acid (DHA)
Abstract
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 ERK and CREB phosphorylation. Together, these findings demonstrate that DLG4 haploinsufficiency disrupts postsynaptic organization, neuronal morphology, and network function in human neurons and provide evidence that DHA may partially restore synaptic and network function in this disorder.
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