Poster abstracts
Poster number 76 submitted by Midhun Anne
Unraveling molecular and cellular mechanisms in a mouse model of SCN8A developmental and epileptic encephalopathy
Midhun N. K. Anne (MCDB), Jason Kaplan (Department of Neuroscience), Laura Kakuk-Atkins (Department of Neuroscience), Jacy L. Wagnon (Department of Neuroscience)
Abstract:
Developmental and epileptic encephalopathies (DEEs) are genetic disorders in humans characterized by drug-resistant seizures along with developmental delay, motor impairment, and neurological deficits. Genome sequencing has identified pathogenic variants in voltage-gated sodium channel alpha subunit genes, including SCN1A and SCN8A, as prominent causes of DEE. The SCN8A gene encodes Nav1.6 protein, which is a pore-forming alpha-subunit of voltage-gated sodium channels that is localized to the axon-initial segments of neurons to initiate and propagate action potentials. A previous mouse model with the patient mutation Scn8a-N1768D exhibited early-seizure onset but did not recapitulate developmental delay and motor impairment seen in the patient. We have developed a conditional mouse model of SCN8A encephalopathy based on a patient mutation that cause severe neonatal-onset seizures and developmental delay. The Scn8a-T767I mouse recapitulates early-onset seizures similar to the proband. Strikingly, Scn8a-T767I mice also exhibit developmental delay and motor impairment along with severely reduced life span. Compared to WT mice, Scn8a-T767I mice showed severe motor impairment demonstrated by delayed or non-existent righting reflex and deficits in several other motor coordination tests. Using neuron type specific-Cre lines and in-vitro studies, our new mouse model will help in understanding the molecular and cellular changes that contribute to developmental delay, epileptogenesis and comorbidities in SCN8A-related DEE.
References:
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Keywords: Voltage-gated sodium channel, Epilepsy, Developmental Delay