Neuronal hyperexcitability in a mouse model of <i>SCN8A</i> epileptic encephalopathy

Abstract

Patients with early infantile epileptic encephalopathy (EIEE) experience severe seizures and cognitive impairment and are at increased risk for sudden unexpected death in epilepsy (SUDEP). EIEE13 [Online Mendelian Inheritance in Man (OMIM) # 614558] is caused by de novo missense mutations in the voltage-gated sodium channel gene <i>SCN8A</i> Here, we investigated the neuronal phenotype of a mouse model expressing the gain-of-function <i>SCN8A</i> patient mutation, p.Asn1768Asp (Na_v1.6-N1768D). Our results revealed regional and neuronal subtype specificity in the effects of the N1768D mutation. Acutely dissociated hippocampal neurons from <i>Scn8a</i>^{<i>N1768D/+</i>} mice showed increases in persistent sodium current (<i>I</i>_Na) density in CA1 pyramidal but not bipolar neurons. In CA3, <i>I</i>_Na,P was increased in both bipolar and pyramidal neurons. Measurement of action potential (AP) firing in <i>Scn8a</i>^{<i>N1768D/+</i>} pyramidal neurons in brain slices revealed early afterdepolarization (EAD)-like AP waveforms in CA1 but not in CA3 hippocampal or layer II/III neocortical neurons. The maximum spike frequency evoked by depolarizing current injections in <i>Scn8a</i>^{<i>N1768D/+</i>} CA1, but not CA3 or neocortical, pyramidal cells was significantly reduced compared with WT. Spontaneous firing was observed in subsets of neurons in CA1 and CA3, but not in the neocortex. The EAD-like waveforms of <i>Scn8a</i>^{<i>N1768D/+</i>} CA1 hippocampal neurons were blocked by tetrodotoxin, riluzole, and SN-6, implicating elevated persistent <i>I</i>_Na and reverse mode Na/Ca exchange in the mechanism of hyperexcitability. Our results demonstrate that <i>Scn8a</i> plays a vital role in neuronal excitability and provide insight into the mechanism and future treatment of epileptogenesis in EIEE13.