Poster abstracts
Poster number 7 submitted by Midhun Anne
Identification of distinct neuronal populations underlying motor impairment in a mouse model of SCN8A epileptic encephalopathy
Midhun Anne (Molecular, Cellular, and Developmental Biology Program, The Ohio State University), Laura Kakuk-Atkins, Jason Kaplan, Robert Ison, Griffin Obermiyer (Department of Neuroscience), Adam Deardorff (Department of Neurology), Stephen Kolb (Department of Neurology), Jacy L. Wagnon (Department of Neuroscience)
Abstract:
The SCN8A gene encodes Nav1.6, an alpha-subunit of voltage-gated sodium channels. Nav1.6 is critical for generation and propagation of neuronal action potentials. Missense variants in SCN8A cause developmental and epileptic encephalopathy (DEE) characterized by seizures, developmental delay, motor impairment, and elevated risk of death. Motor impairment, including hypotonia and movement disorders, is the most common comorbidity and significantly impacts quality of life. The underlying cause of motor impairment in SCN8A DEE is not clear. Previous mouse models of SCN8A DEE recapitulated seizures but lacked motor dysfunction. We developed a new mouse model of SCN8A DEE with an inducible allele of the patient variant p.Thr767Ile (T767I). Global neuronal expression of T767I with Sox2-cre (Scn8a-T767I/+) resulted in early-onset seizures and premature lethality. Importantly, Scn8a-T767I/+ mice also exhibited motor impairment, including righting delay, muscle weakness, and altered gait. Mice expressing T767I only in excitatory neurons (Emx1-Cre) had seizures but did not exhibit motor impairment, indicating that the neuronal mechanisms underlying seizures are distinct from those underlying motor impairment. Electrophysiological recordings from muscle of Scn8a-T767I/+ mice revealed reduced compound muscle action potentials and fewer functional motor units, suggesting that abnormal motor neuron activity contributes to motor impairment. We are now utilizing motor network specific Cre lines to delineate neuronal circuits that contribute to motor impairment in SCN8A DEE. Using ChAT-Cre, we observe delayed righting, indicating that T767I expression in lower motor neurons may contribute to impaired motor development. Expression of T767I in cerebellar Purkinje neurons (Pcp2-Cre) results in uncoordinated gait, suggesting that altered cerebellar signaling is also involved. Overall, our studies show that the Scn8a-T767I/+ mouse is the first model of SCN8A DEE to recapitulate motor impairment. We have identified distinct neuronal populations contributing to motor dysfunction. Our ongoing studies will help determine the pathogenic neuronal mechanisms underlying motor impairment in SCN8A DEE.
References:
1. Specchio N, Curatolo P. Developmental and epileptic encephalopathies: what we do and do not know. Brain. 2021 Feb 12;144(1):32-43. doi: 10.1093/brain/awaa371. PMID: 33279965.
2. Veeramah KR, O'Brien JE, Meisler MH, et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet. 2012;90(3):502-510. doi:10.1016/j.ajhg.2012.01.006
3. Estacion M, O'Brien JE, Conravey A, et al. A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. Neurobiol Dis. 2014;69:117-123. doi:10.1016/j.nbd.2014.05.017
Keywords: SCN8A, Developmental and epileptic encephalopathy, Motor impairment