Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

Stacey B.B Dutton,Karoni Dutt,Ligia A Papale,Sandra Helmers,Alan L Goldin,Andrew Escayg

doi:10.1016/j.expneurol.2017.03.026

Abstract

Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A, encoding the Nav1.1 channel, are responsible for a number of epilepsy disorders including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS). Patients with SCN1A mutations often experience prolonged early-life febrile seizures (FSs), raising the possibility that these events may influence epileptogenesis and lead to more severe adult phenotypes. To test this hypothesis, we subjected 21–23-day-old mice expressing the human SCN1A GEFS+ mutation R1648H to prolonged hyperthermia, and then examined seizure and behavioral phenotypes during adulthood. We found that early-life FSs resulted in lower latencies to induced seizures, increased severity of spontaneous seizures, hyperactivity, and impairments in social behavior and recognition memory during adulthood. Biophysical analysis of brain slice preparations revealed an increase in epileptiform activity in CA3 pyramidal neurons along with increased action potential firing, providing a mechanistic basis for the observed worsening of adult phenotypes. These findings demonstrate the long-term negative impact of early-life FSs on disease outcomes. This has important implications for the clinical management of this patient population and highlights the need for therapeutic interventions that could ameliorate disease progression.

Highlights

Febrile seizures (FSs) are convulsions triggered by high fever
Age-dependent susceptibility to hyperthermia-induced seizures were identified in the Scn1a mouse model of Dravet syndrome (DS) (Oakley et al, 2009) and these seizures were alleviated with the combined therapy of the anti-seizure drugs clonazepam and tiagabine (Oakley et al, 2013)
We investigated the effect of early-life FSs on the development of epilepsy using a mouse line that expresses the human SCN1A GEFS+ mutation R1648H

Summary

Introduction

Febrile seizures (FSs) are convulsions triggered by high fever. They are the most common type of pediatric seizure, affecting 2–5% of children between 6 months and 5 years of age in the United States (Shinnar and Glauser, 2002). Retrospective studies of resected brain tissue from adults with temporal lobe epilepsy (TLE) suggest a strong correlation between the development of TLE and early-life FSs (Falconer et al, 1964; French et al, 1993). Studies conducted by Cendes et al (1993) found that the prevalence of TLE exhibiting mesial temporal sclerosis is higher in patients with a history of complex early-life FSs. In addition, studies conducted by Cendes et al (1993) found that the prevalence of TLE exhibiting mesial temporal sclerosis is higher in patients with a history of complex early-life FSs These studies did not establish whether the development of epilepsy was a consequence of the early-life FSs or a manifestation of the disease presentation. Mutations in SCN1A, the gene encoding the α-subunit of the Nav1.1 voltage-gated sodium channel, are responsible for several epilepsy disorders,

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Conclusion