SynGAP splice isoforms differentially regulate synaptic plasticity and dendritic development

SynGAP is a synaptic Ras GTPase-activating protein (GAP) with four C-terminal splice variants: α1, α2, β, and γ. Although recent studies have implicated SYNGAP1 haploinsufficiency in ID/ASD pathogenesis, the degree to which each SynGAP isoform contributes to disease pathogenesis remains elusive. Here we demonstrate that individual SynGAP isoforms exhibit unique spatiotemporal expression and have distinct roles in neuronal and synaptic development. The SynGAP-α1 isoform, which undergoes robust liquid-liquid phase-separation with PSD-95 and is highly-enriched in synapses, is expressed late in development and disperses from synaptic spines in response to LTP-inducing synaptic activity to allow for AMPA receptor insertion and spine enlargement. In contrast, the SynGAP-β isoform, which undergoes less liquid-liquid phase-separation with PSD95 and is less synaptically targeted, is expressed early in development and promotes dendritic arborization. Interestingly, a SynGAP-α1 mutation that disrupts phase separation and synaptic targeting abolishes its function in plasticity and instead drives dendritic arbor development like the β isoform. These results demonstrate that distinct phase separation and synaptic targeting properties of SynGAP isoforms determine their function. Highlights 1. SynGAP-α1, α2, β, γ isoforms have distinct spatiotemporal expression and function in the brain. 2. SynGAP-α1 is required for plasticity, while β is required for dendritic development. 3. Liquid-liquid phase separation of SynGAP-α1 is required for its role in plasticity. 4. SynGAP isoforms may differentially contribute to SYNGAP1 related human NDDs.