Epilepsy and neuropsychiatric comorbidities in mice carrying a recurrent Dravet syndrome SCN1A missense mutation

Ana Ricobaraza,Elena Puerta,Miguel Valencia,Noemi Sola-Sevilla,Maria Bunuales,Maria Jesus Nicolas,Guillermo Besne,Rocio Sanchez-Carpintero,Lucia Mora-Jimenez,Manuela Gonzalez-Aparicio,Ana Mingorance,Julio Artieda,Ruben Hernandez-Alcoceba

doi:10.1038/s41598-019-50627-w

Abstract

Dravet Syndrome (DS) is an encephalopathy with epilepsy associated with multiple neuropsychiatric comorbidities. In up to 90% of cases, it is caused by functional happloinsufficiency of the SCN1A gene, which encodes the alpha subunit of a voltage-dependent sodium channel (Nav1.1). Preclinical development of new targeted therapies requires accessible animal models which recapitulate the disease at the genetic and clinical levels. Here we describe that a C57BL/6 J knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V) presents a full spectrum of DS manifestations. This includes 70% mortality rate during the first 8 weeks of age, reduced threshold for heat-induced seizures (4.7 °C lower compared with control littermates), cognitive impairment, motor disturbances, anxiety, hyperactive behavior and defects in the interaction with the environment. In contrast, sociability was relatively preserved. Electrophysiological studies showed spontaneous interictal epileptiform discharges, which increased in a temperature-dependent manner. Seizures were multifocal, with different origins within and across individuals. They showed intra/inter-hemispheric propagation and often resulted in generalized tonic-clonic seizures. 18F-labelled flourodeoxyglucose positron emission tomography (FDG-PET) revealed a global increase in glucose uptake in the brain of Scn1aWT/A1783V mice. We conclude that the Scn1aWT/A1783V model is a robust research platform for the evaluation of new therapies against DS.

Highlights

Dravet Syndrome (DS) is an encephalopathy with epilepsy associated with multiple neuropsychiatric comorbidities
Mice from the B6.C-Tg(CMV-Cre)1Cgn/J strain express Cre under the control of the ubiquitous CMV promoter. When these strains are crossed, the floxed exon can suffer Cre-mediated scission and the mutated exon 26 is incorporated in the mature mRNA expressed from this allele. This happens in approximately half of the offspring
DS is a complex encephalopathy affecting the inhibition/excitation balance in the brain, which explains the wide repertoire of clinical manifestations

Summary

Introduction

Dravet Syndrome (DS) is an encephalopathy with epilepsy associated with multiple neuropsychiatric comorbidities. We describe that a C57BL/6 J knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V) presents a full spectrum of DS manifestations This includes 70% mortality rate during the first 8 weeks of age, reduced threshold for heat-induced seizures (4.7 °C lower compared with control littermates), cognitive impairment, motor disturbances, anxiety, hyperactive behavior and defects in the interaction with the environment. In nearly 90% of DS patients, the genetic basis of the disease involves the SCN1A gene[5,6], which encodes the alpha subunit of a voltage-dependent sodium channel (Nav1.1). This membrane transporter is crucial for the function of GABAergic inhibitory interneurons expressing parvalbumin or somatostatin (PV and ST cells, respectively)[7,8]. Diverse functional alterations of Nav1.1 may contribute to other neurological disorders such as autism[12], familial hemiplegic migraine[13], and aging-related cerebral impairment[14]

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