Les mutations du gène SCN1A, sont impliquées dans des épilepsies du nourrisson : le Syndrome de Dravet (SD), une épilepsie rare et pharmaco-résistante ou l’Epilepsie généralisée avec crises fébriles plus (GEFS+), une épilepsie plus légère. GEFS+ et SD sont associés à des crises épileptiques fébriles dès l’âge de 6 mois. Dans le SD on voit apparaitre des retards mentaux mais également des déficits moteurs, visuels, langagiers et mnésiques au cours de l’évolution de la maladie. L’impact des crises épileptiques au cours l’enfance sur ces déficits cognitifs n’est pas connu. Le SD est considéré comme une encéphalopathie épileptique où les crises étaient les principales responsables du phénotype à l’âge adulte. Récemment, un rôle potentiel de la mutation dans les troubles cognitifs a été mis en évidence changeant la définition de SD d’encéphalopathie épileptique à une canalopathie. La question est quel est le rôle des crises épileptiques répétées sur les fonctions cognitives à l’âge adulte ? Nous avons utilisé un modèle murin de la maladie portant une mutation du gène Scn1a, et qui présente une pathologie très légère. Nous avons induit des crises épileptiques par hyperthermie à l’âge de 21 jours (10 jours) et testé les effets à long-terme à l’âge adulte. Nos résultats révèlent que l’induction de crises induit une hyperactivité, des altérations dans les interactions sociales et des déficits en mémoires hippocampo et cortex préfronto-dépendantes. Ainsi nous avons mis en évidence que les crises épileptiques répétées pendant le développement ont un fort impact sur la fonction cérébrale et qu’il est donc capital de les prévenir afin de diminuer, voir de prévenir, ces déficits. / The SCN1A gene codes for the voltage-gated sodium channel Nav1.1 α-subunit. SCN1A mutations cause genetic epilepsies, as Generalized Epilepsy with Febrile Seizures plus (GEFS+), a mild epilepsy, or Dravet Syndrome (DS), a rare, severe and drug-resistant epileptic encephalopathy (EE). DS patients show severe cognitive/behavioral impairments that, according to the definition of EE, should be caused by the recurrent epileptic activity. Yet, this causal relationship has never been proved and it is been challenged by studies in mouse models showing that the genetic mutation itself, which causes a decrease in GABAergic activity, can be responsible for DS cognitive outcome. We studied the implication of repeated seizures during childhood to the later long-term modifications on cognitive/behavioral and epileptic phenotypes by submitting the Scn1a mouse model carrying the R1648H missense mutation and presenting mild phenotype to a protocol of repeated seizures induction by hyperthermia (10 days/one seizure per day). We observed that early life seizures can worsen the epileptic phenotype and induce cognitive/behavioral defects notably by inducing hyperactivity, sociability deficits and hippocampus- and prefrontal cortex-dependent memory deficits. We found that early life seizures can worsen the epileptic phenotype and induce cognitive/behavioral defects. Although the effect of NaV1.1 dysfunction in altering brain synchrony and the effect of repeated seizure activity in the young brain are not mutually exclusive, we thus conclude that epileptic seizures are sufficient to convert a Scn1a mouse model carrying a mild phenotype into a severe phenotype.

Genetic epilepsy with febrile seizures plus (GEFS+) is associated with a wide range of neurological dysfunction caused in part by limited function in voltage-gated sodium channels (Escayg & Goldin, 2010; Gambardella & Marini, 2009; Mulley et al., 2005). The seizure and behavioral phenotypes, as well as use of non-pharmacologic agents as neuroprotectants in GEFS+, are not well-understood. An experimental design used an animal model of GEFS+ to 1. explore the effects of stress on seizure phenotype, 2. examine behavioral phenotypes, and 3. study the effects of an omega 3 fatty acid on abnormal behaviors noted in the various paradigms. This study used C57BL/6J mice with the R1648H missense mutation on the Scn1a gene (engineered in the Escayg lab) (Martin, M. S. et al., 2010). The three specific aims used separate groups of animals for experimentation, and all paradigms were performed under strict laboratory conditions. Data were analyzed using either an independent t-tests, two-way ANOVA or repeated measures two-way ANOVA. Results showed that stress worsens seizure phenotype in both the Scn1aR1648H (RH) mutants and wild-type (WT) group with the RH mutants more severely impacted. In addition, there was clear and consistent evidence for hyperactive locomotor behavior. Lastly, no evidence was found for use of docosahexaenoic acid (DHA, an omega 3 fatty acid) as a neuroprotectant for hyperactivity (DHA was given subcutaneously for two weeks starting at weaning). Outcomes from this study implicate that stress worsens the seizure phenotype in animals with Scn1aR1648H. This study is also the first to report hyperactive locomotor behavior in animals with Scn1aR1648H. Results from this study may broaden beyond GEFS+ in that we may also be able to apply the findings to other disorders with SCN1A dysfunction. In addition, it may be that genetic variants affecting SCN1A, but not necessarily in epilepsy, may contribute to hyperactivity. This could mean that SCN1A is a candidate gene for hyperactivity. The main goal of nursing care is to reduce and prevent disease morbidity, and knowledge gained from the current study will guide clinical nursing practice, such as targeted behavioral assessment and education, as well as nursing research focusing on children with this genetic disorder.