Understanding the role of SCN8A in developmental and epileptic encephalopathy

PROJECT SUMMARY Developmental and epileptic encephalopathies (DEEs) are severe early-onset seizure disorders with treatment-resistant seizures, developmental delay/regression, and long-term cognitive and motor impairment. SCN8A DEE, caused by gain-of-function, missense variants in the voltage-gated sodium channel gene SCN8A (Nav1.6), is characterized by infantile-onset seizures, mild to severe intellectual disability, significant developmental delay, and elevated risk of premature lethality. A serious comorbidity in SCN8A DEE is the prominent motor impairment, including severe hypotonia, movement disorders, and a large proportion of individuals that are non-ambulatory. Two mouse models carrying the patient mutations p.Asn1768Asp (N1768D) or p.Arg1872Trp (R1872W) recapitulated seizures and early death but did not exhibit motor impairment. Thus, insight into the mechanisms underlying motor impairment in SCN8A DEE has not previously been possible. We developed a novel conditional mouse model of SCN8A DEE with the patient mutation p.Thr767Ile (T767I). The T767I mouse is the first model of SCN8A DEE that exhibits significant muscle weakness and motor impairment. Our preliminary data suggests that functional motor units are reduced in Scn8a-T767I/+ mice. We hypothesize that the Scn8a-T767I mutation alters spinal motor neuron activity, leading to dysfunction of the motor unit and motor impairment in SCN8A DEE. Thus, we propose to use this unique mouse model to address the gap in our understanding of the pathophysiology underlying motor impairment in SCN8A DEE. We will use the T767I mouse to 1) determine how Scn8a-T767I affects motor unit structure, function and connectivity, 2) determine how expression of Scn8a-T767I in motor neurons affects neuromotor development, and 3) determine whether motor impairment can be prevented or reversed with administration of an anti-sense oligonucleotide that reduces expression of Scn8a in brain and spinal cord. Information gained from these studies will provide mechanistic insight into the pathophysiology of SCN8A DEE that will aid in the development of new therapeutic strategies for this severe disorder.