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.