Distinct neuronal mechanisms for motor impairment and seizures in a novel mouse model of SCN8A epileptic encephalopathy.

Variants in the voltage-gated sodium channel gene SCN8A cause a severe developmental and epileptic encephalopathy (DEE) characterized by treatment-resistant seizures, developmental delay, long-term cognitive and motor impairment, and elevated risk of premature death. The most common comorbidity is motor impairment, including hypotonia, movement disorders like ataxia, and weakness. To date, mouse models of SCN8A DEE have recapitulated seizures and early death, but have not exhibited motor impairment. We developed a novel conditional mouse model of SCN8A DEE with the patient mutation p.Thr767Ile (T767I). Ubiquitous expression of the T767I allele with Sox2-Cre (Scn8aT767I/+) results in neuronal hyperexcitability, spontaneous convulsive seizures, and premature death in heterozygotes. Scn8aT767I/+ mice also exhibit significant early-onset motor impairment and muscle weakness. Mice with expression of the T767I allele in excitatory neurons driven by Emx1-Cre experience seizures and early death but do not exhibit motor impairment, indicating that the neuronal mechanisms underlying seizures are distinct from the mechanisms underlying motor impairment. Compound muscle action potentials are smaller, and the number of functional motor units is reduced in Sox2-Cre, Scn8aT767I/+ mice, suggesting that motor neuron function is affected by the T767I mutation. Neuromuscular junctions exhibit morphological abnormalities and appear to have delayed maturation in Scn8aT767I/+ mice compared to Scn8a+/+ mice. The Scn8aT767I/+ mouse is the first model of SCN8A DEE to recapitulate motor impairment. This novel mouse model will permit elucidation of the pathogenic mechanisms underlying motor impairment in SCN8A DEE.