Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

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.

Influence of contraindicated medication use on cognitive outcome in Dravet syndrome and age at first afebrile seizure as a clinical predictor in SCN1A‐related seizure phenotypes

“…Although reliable data on seizure frequency during CIM use are not available for our cohort, increases in seizure frequency due to sodium channel blocker use have been reported previously . High seizure frequency has been associated with a worse cognitive outcome in Dravet syndrome patients, and similar findings have recently been shown in SCN1A + mice . Furthermore, if CIM is used, indicated medication is less likely to be prescribed, and therefore the negative effects of CIM can also partly be due to the deprivation of optimal treatment.…”

“…6,27,28 High seizure frequency has been associated with a worse cognitive outcome in Dravet syndrome patients, 26,37 and similar findings have recently been shown in SCN1A+ mice. 38 Furthermore, if CIM is used, indicated medication is less likely to be prescribed, and therefore the negative effects of CIM can also partly be due to the deprivation of optimal treatment. It is therefore likely that an increased seizure severity, at least to some extent, explains the worse cognitive outcome associated with longer CIM use, in accordance with the epileptic encephalopathy disease model.…”

Hyperthermia‐induced seizures followed by repetitive stress are associated with age‐dependent changes in specific aspects of the mouse stress system

“…Indeed, it has been reported that ELS protocols impair various behavioural domains, including memory; incidentally, ELS effects are generally much more prominent in male than in female rodents, which is one of the reasons why we restricted the present study to male mice only. Likewise, HT‐induced seizures affect memory performance later in life, although the results so far were somewhat equivocal . Most likely, the combination will have impact on behaviour, although this assumption clearly requires dedicated experiments to be substantiated.…”

Reduced cannabinoid 2 receptor activity increases susceptibility to induced seizures in mice

“…40 Briefly, mice were placed in a plexiglass chamber (13.5 × 8 × 6 inches), and exposed to flurothyl (bis[2,2,2-trifluoroethyl] ether, Sigma-Aldrich) at a rate of 20 µL/min. 40 Briefly, mice were placed in a plexiglass chamber (13.5 × 8 × 6 inches), and exposed to flurothyl (bis[2,2,2-trifluoroethyl] ether, Sigma-Aldrich) at a rate of 20 µL/min.…”

“…Thresholds to flurothyl-induced seizures were determined as previously described. 40 Briefly, mice were placed in a plexiglass chamber (13.5 × 8 × 6 inches), and exposed to flurothyl (bis[2,2,2-trifluoroethyl] ether, Sigma-Aldrich) at a rate of 20 µL/min. Latencies to the first MJ and GTCS were recorded (n = 8-12/group).…”