Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy

Abstract

Heterozygous loss-of-function mutations in the ␣ subunit of the type I voltage-gated sodium channel NaV1.1 cause severe myoclonic epilepsy in infancy (SMEI), an infantile-onset epileptic encephalopathy characterized by normal development followed by treatment-refractory febrile and afebrile seizures and psychomotor decline. Mice with SMEI (mSMEI), created by heterozygous deletion of NaV1.1 channels, develop seizures and ataxia. Here we investigated the temperature and age dependence of seizures and interictal epileptiform spikeand-wave activity in mSMEI. Combined video-EEG monitoring demonstrated that mSMEI had seizures induced by elevated body core temperature but wild-type mice were unaffected. In the 3 age groups tested, no postnatal day (P)17-18 mSMEI had temperature-induced seizures, but nearly all P20 -22 and P30 -46 mSMEI had myoclonic seizures followed by generalized seizures caused by elevated core body temperature. Spontaneous seizures were only observed in mice older than P32, suggesting that mSMEI become susceptible to temperature-induced seizures before spontaneous seizures. Interictal spike activity was seen at normal body temperature in most P30 -46 mSMEI but not in P20 -22 or P17-18 mSMEI, indicating that interictal epileptic activity correlates with seizure susceptibility. Most P20 -22 mSMEI had interictal spike activity with elevated body temperature. Our results define a critical developmental transition for susceptibility to seizures in SMEI, demonstrate that body temperature elevation alone is sufficient to induce seizures, and reveal a close correspondence between human and mouse SMEI in the striking temperature and age dependence of seizure frequency and severity and in the temperature dependence and frequency of interictal epileptiform spike activity.Dravet syndrome ͉ febrile seizures ͉ generalized tonic-clonic seizures ͉ sodium channels ͉ SCN1A

Specific deletion of Na V 1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome

“…4C). The pattern of epileptiform electrical activity preceding and during the seizures induced in F/+:Dlx-Cre + mice was similar to those characterized previously in global Na V 1.1 heterozygotes (14,15) …”

“…These global heterozygous mice exhibit temperature-induced and spontaneous seizures, mild ataxia, and premature death (14)(15)(16). Na V 1.1 channels are expressed in both excitatory and inhibitory neurons (3,6), yet electrophysiological studies in dissociated hippocampal neurons from DS mice showed selective loss of sodium current and excitability in GABAergic interneurons (14,17).…”

Novel Animal Models of Pediatric Epilepsy

“…A first animal model of DS has been generated in mice through a targeted deletion of a major exon in the SCN1A gene [137]. Homozygous null Scn1a−/− mice developed ataxia and died around P15, whereas heterozygous Scn1a1/-mice had hyperthermic-induced seizures and spontaneous seizures [137].…”

“…Homozygous null Scn1a−/− mice developed ataxia and died around P15, whereas heterozygous Scn1a1/-mice had hyperthermic-induced seizures and spontaneous seizures [137]. A second mouse model has been generated through knock-in of a stop codon into the SCN1A gene (R1407X, in exon 21) [138].…”

“…The interictal recordings permit further illustration of these developmental changes in the seizure susceptibility. Most of the P20-P22 mice have interictal epileptic activity with elevated body temperature, whereas interictal activity was observed at normal temperature in most of the P30-P46 mice [137]. In the second model, the authors reported that homozygous knock-in (Scn1aRX/RX) pups developed recurrent spontaneous seizures at P12.…”