Heat induced temperature dysregulation and seizures in Dravet Syndrome/GEFS+ Gabrg2+/Q390X mice

Abstract

<p class="first" id="P1">It has been established that febrile seizures and its extended syndromes like generalized epilepsy with febrile seizures (FS) plus (GEFS+) and Dravet syndrome have been associated with mutations especially in <i>SCN1A</i> and <i>GABRG2</i> genes. In patients, the onset of FS is likely due to the combined effect of temperature and inflammation in genetically vulnerable individuals because fever is often associated with infection. Much effort has been spent to understand the mechanisms underlying fever induction of seizures. In addition to the role of cytokines in FS, previous studies in <i>Scn1a ^+/− </i> knockout mice, a model of Dravet syndrome, indicated that temperature elevation alone could result in seizure generation, and the effect of elevated temperature inducing seizures was age-dependent. Here, we report the thermal effect in a different mouse model of Dravet syndrome, the <i>Gabrg2 ^+/Q390X </i> knockin mouse. We demonstrated age-dependent dysregulated temperature control and that temperature elevation produced myoclonic jerks, generalized tonic clonic seizures (GTCSs) and heightened anxietylike symptoms in <i>Gabrg2 ^+/Q390X </i> mice. The study indicated that regardless of other inflammatory factors, brief heat alone increased brain excitability and induced multiple types of seizures in <i>Gabrg2 ^+/Q390X </i> mice, suggesting that mutations like <i>GABRG2</i>( <i>Q390X</i>) may alter brain thermal regulation and precipitate seizures during temperature elevations. </p>