Gamache, T. R. | Search bioRxiv

bioRxiv2023

SynGAP regulates synaptic plasticity and cognition independent of its catalytic activity

SynGAP is an abundant synaptic GTPase-activating protein (GAP) critical for synaptic plasticity, learning, memory, and cognition. Mutations in SYNGAP1 in humans result in intellectual disability, autistic-like behaviors, and epilepsy. Heterozygous Syngap1 knockout mice display deficits in synaptic plasticity, learning, and memory, and exhibit seizures. It is unclear whether SynGAP imparts structural properties at synapses independent of its GAP activity. Here, we report that inactivating mutations within the SynGAP GAP domain do not inhibit synaptic plasticity or cause behavioral deficits. Instead, SynGAP modulates synaptic strength by physically competing with the AMPA- receptor-TARP complex, the major excitatory receptor complex in the brain, in the formation of molecular condensates with synaptic scaffolding proteins. These results have significant implications for the development of therapeutic treatments for SYNGAP1- related neurodevelopmental disorders. One-Sentence SummarySynGAP regulates synaptic plasticity and cognition due to its phase separation properties instead of its catalytic activity.

neuroscience↗

bioRxiv2020

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: 1, 2, {beta}, and {gamma}. 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-1 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-{beta} 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-1 mutation that disrupts phase separation and synaptic targeting abolishes its function in plasticity and instead drives dendritic arbor development like the {beta} isoform. These results demonstrate that distinct phase separation and synaptic targeting properties of SynGAP isoforms determine their function. HighlightsO_LISynGAP-1, 2, {beta}, {gamma} isoforms have distinct spatiotemporal expression and function in the brain. C_LIO_LISynGAP-1 is required for plasticity, while {beta} is required for dendritic development. C_LIO_LILiquid-liquid phase separation of SynGAP-1 is required for its role in plasticity. C_LIO_LISynGAP isoforms may differentially contribute to SYNGAP1 related human NDDs. C_LI

neuroscience↗