Heat-induced seizures, premature mortality, and hyperactivity in a novelScn1anonsense model for Dravet syndrome

AbstractDravet syndrome (Dravet) is a severe congenital developmental genetic epilepsy caused byde novomutations in theSCN1Agene. Nonsense mutations are found in ~20% of the patients, and the R613X mutation was identified in multiple patients. Here we characterized the epileptic and non-epileptic comorbidities of a novel preclinical Dravet mouse model harboring this nonsenseScn1amutation. HeterozygousScn1aR613X mutation on a mixed C57BL/6J:129S1/SvImJ background exhibited spontaneous seizures, susceptibility to heat-induced seizures, and premature mortality, recapitulating the core epileptic phenotypes of Dravet. In addition, these mice, available as an open-access model, demonstrated increased locomotor activity in the open-field test, mimicking some non-epileptic Dravet-associated comorbidities. Conversely,Scn1aWT/R613Xmice on the pure 129S1/SvImJ background had a normal life span and were easy to breed. HomozygousScn1aR613X/R613Xmice died before P16.Our molecular analyses of hippocampal and cortical expression demonstrated that the premature stop codon induced by the R613X mutation reducedScn1amRNA and Nav1.1 protein levels to ~50% in heterozygousScn1aWT/R613Xmice, with marginal expression in homozygousScn1aR613X/R613Xmice. Together, we introduce a novel Dravet model carrying the R613XScn1anonsense mutation that can. be used to study the molecular and neuronal basis of Dravet, as well as the development of new therapies associated withSCN1Anonsense mutations in Dravet.