Dissociation of SYNGAP1 Enzymatic and Structural Roles: Intrinsic Excitability and Seizure Susceptibility

Abstract

SYNGAP1 is a key Ras-GAP protein enriched at excitatory synapses, with mutations causing intellectual disability and epilepsy in humans. Recent studies have revealed that in addition to its role as a negative regulator of G-protein signaling through its GAP enzymatic activity, SYNGAP1 plays an important structural role through its interaction with post-synaptic density proteins. Here, we reveal that intrinsic excitability deficits and seizure phenotypes in heterozygous Syngap1 knockout (KO) mice are differentially dependent on Syngap1 GAP activity. Cortical excitatory neurons in heterozygous KO mice displayed reduced intrinsic excitability, including lower input resistance, and increased rheobase, a phenotype recapitulated in GAP-deficient Syngap1 mutants. However, seizure severity and susceptibility to pentylenetetrazol (PTZ)-induced seizures were significantly elevated in heterozygous KO mice but unaffected in GAP-deficient mutants, implicating the structural rather than enzymatic role of Syngap1 in seizure regulation. These findings highlight the complex interplay between SYNGAP1 structural and catalytic functions in neuronal physiology and disease. Significance StatementMutations in the SYNGAP1 gene are a major cause of intellectual disability, autism, and epilepsy. The SYNGAP1 protein is an important constituent of postsynaptic specializations, and two distinct functions have been characterized: a structural function, carried by its C-terminal PDZ domain, that organizes the composition of the postsynaptic density, and an enzymatic function, in which its GAP domain negatively regulates small GTPases. So far, no electrophysiological/behavioral phenotype of SYNGAP1 has been directly linked to the GAP catalytic activity. Here, we describe that while the GAP catalytic activity does not contribute to the increased seizure susceptibility seen in SYNGAP1 haploin-sufficiency, it does regulate the intrinsic excitability of upper lamina pyramidal cells.