Severe Myoclonic Epilepsy in Infancy (SMEI) is a devastating, infantile-onset, inherited, epilepsy syndrome that has no effective treatment. It is associated with loss-of-function mutations in SCN1A which codes for a voltage-gated sodium channel Nav1.1 expressed in central neurons and important for the excitability of cells. Seizure type and severity in SMEI depend on age and can be provoked with elevated body temperature. This research project will focus on understanding brain regions which are important in seizure initiation as a function of age and body temperature in severe myoclonic epilepsy in infancy, two critical factors that we have recently demonstrated are important in determining seizure susceptibility. Region specific excitability as a function of age and body temperature will be determined in a previously developed mouse model of SMEI (mSMEI) containing a whole animal heterozygous deletion of the Nav1.1 voltage gated sodium channel and in a newly created cortical and hippocampal GABAergic interneuron specific heterozygote Nav1.1 deleted mouse (IS-mSMEI). The proposed experiments will determine in vivo excitability changes in the hippocampus and cortex with combined cortical surface and hippocampal depth electrode EEG recording and determine changes in in vitro excitability using field potential recording in a well-established slice model, a combined hippocampal- entorhinal cortex slice. These studies will provide critical information regarding the brain regions involved in seizures in SMEI, how excitability in those brain regions might change as a function of age and body temperature, and whether GABAergic interneuron specific Nav1.1 deletion is sufficient to produce the SMEI seizure phenotype.

Public Health Relevance

Severe Myoclonic Epilepsy in Infancy (SMEI) is a devastating infantile-onset, inherited epilepsy syndrome that is refractory to current therapies. Children with SMEI are normal at birth but develop seizures of multiple types and increasing severity with age, frequently provoked by elevated body temperature. In this Mentored Clinician-Scientist Career Development Award (K08), Dr. Oakley will develop skills required to become an independent investigator using a mouse model of SMEI to understand what brain regions are critically involved in seizures as a function of age and body temperature.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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Stewart, Randall R
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University of Washington
Schools of Medicine
United States
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Oakley, John C; Cho, Alvin R; Cheah, Christine S et al. (2013) Synergistic GABA-enhancing therapy against seizures in a mouse model of Dravet syndrome. J Pharmacol Exp Ther 345:215-24
Cheah, Christine S; Westenbroek, Ruth E; Roden, William H et al. (2013) Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome. Channels (Austin) 7:468-72
Kalume, Franck; Westenbroek, Ruth E; Cheah, Christine S et al. (2013) Sudden unexpected death in a mouse model of Dravet syndrome. J Clin Invest 123:1798-808