Proceedings of the National Academy of Sciences of the United States of AmericaFeb 15, 2017

Increased nerve cell activity in a mouse model of SCN8A-related severe epilepsy

Updated Feb 3, 2026

Abstract

Mice with the p.Asn1768Asp mutation in the sodium channel gene showed significant changes in neuronal excitability, particularly in CA1 hippocampal neurons.

The mutation was associated with increased persistent sodium current density in CA1 pyramidal neurons but not in bipolar neurons.
Increased persistent sodium current density was observed in both bipolar and pyramidal neurons in the CA3 region.
CA1 pyramidal neurons exhibited early afterdepolarization-like action potential waveforms, while CA3 and neocortical neurons did not.
Maximum spike frequency in CA1 pyramidal cells was significantly reduced compared to wild type, indicating altered excitability.
Spontaneous firing occurred in subsets of neurons in CA1 and CA3 regions, but was absent in the neocortex.
The EAD-like waveforms in CA1 neurons were blocked by tetrodotoxin, riluzole, and SN-6, suggesting mechanisms related to elevated persistent sodium currents.

Simplified

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 geneHere, we investigated the neuronal phenotype of a mouse model expressing the gain-of-functionpatient mutation, p.Asn1768Asp (Na1.6-N1768D). Our results revealed regional and neuronal subtype specificity in the effects of the N1768D mutation. Acutely dissociated hippocampal neurons frommice showed increases in persistent sodium current () density in CA1 pyramidal but not bipolar neurons. In CA3,was increased in both bipolar and pyramidal neurons. Measurement of action potential (AP) firing inpyramidal 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 inCA1, 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 ofCA1 hippocampal neurons were blocked by tetrodotoxin, riluzole, and SN-6, implicating elevated persistentand reverse mode Na/Ca exchange in the mechanism of hyperexcitability. Our results demonstrate thatplays a vital role in neuronal excitability and provide insight into the mechanism and future treatment of epileptogenesis in EIEE13. SCN8A SCN8A Scn8a I I Scn8a Scn8a Scn8a I Scn8a v Na Na,P Na N1768D/+ N1768D/+ N1768D/+ N1768D/+

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The authors declare no conflict of interest.

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