SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity

Abstract

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