Poster abstracts
Poster number 84 submitted by Midhun Anne
Delineating neuronal circuits contributing to seizures and motor comorbidities in a mouse model of SCN8A DEE
Midhun Anne (MCDB), Jason Kaplan (Department of Neuroscience), Laura Kakuk-Atkins (Department of Neuroscience), Robert Ison (Department of Neuroscience), Griffin Obermiyer (Department of Neuroscience), Jacy L. Wagnon (Department of Neuroscience)
Abstract:
Developmental and epileptic encephalopathies (DEEs) are a class of genetic epilepsy disorders characterized by treatment-resistant seizures, cognitive impairment, developmental delay, and motor impairment. Pathogenic missense variants sodium channel gene SCN8A cause severe DEE. The SCN8A gene encodes Nav1.6 protein, a pore-forming alpha-subunit of voltage-gated sodium channels that is localized to the axon-initial segments of neurons and mature nodes of Ranvier to initiate and propagate action potentials. SCN8A DEE mutations cause gain-of-function (GOF) biophysical effects in Nav1.6 channel activity. For example, the variant p.Thr767Ile (T767I) causes premature channel activation leading to neuronal hyperexcitability. Previous mouse models of SCN8A DEE recapitulated early-seizure onset, but they lacked motor comorbidities, hindering the investigation of how neuronal hyperexcitability causes motor impairment in SCN8A DEE. In our new conditional mouse model of SCN8A DEE, which has an inducible T767I allele, global neuronal activation of T767I with Sox2-cre caused early-seizure onset. Strikingly, Scn8a-T767I/+ mice also exhibit developmental delay and motor impairment. Compared to WT mice, Scn8a-T767I/+ mice showed severe motor impairment demonstrated by delayed righting reflex and deficits in other motor coordination tests. Muscle electrophysiological recordings of Scn8a-T767I/+ mice showed reduced motor neuron activity. By targeting T767I mutation only to a subset of forebrain excitatory neurons (Emx1-cre), we discovered that expression of T767I allele in these neurons contribute to seizures but not to the motor comorbidities seen in the Scn8a-T767I/+ (Sox2-cre) mice. We are currently investigating whether myelination is perturbed in our mouse model of SCN8A DEE. Further using other neuron type specific-Cre lines, our new mouse model will help in delineating neuronal circuits contributing to comorbidities in DEE and understanding how neuron-glia and neuron-muscle communication plays a role in SCN8A DEE.
References:
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Keywords: SCN8A epilepsy, Developmental and epileptic encephalopathy, Developmental delay