Mutations of the GABA--A receptor (GABAAR) alpha 1 subunit have recently been associated with idiopathic generalized epilepsy (IGE) syndromes. Neurons increase the expression of the alpha 1 subunit at the times in development when the symptoms of the IGE syndromes typically arise. Our long term goal is to understand how these mutations disrupt GABAAR expression and physiology at specific times in development in order to provide a mechanistic basis for the development of new treatment and prevention strategies for these epilepsy syndromes and their co-morbid conditions. The hypotheses to be tested are: 1) because 11 subunit expression increases throughout development, GABRA1 epilepsy mutations will reduce total GABAAR subunit protein and produce neurons with smaller IPSC amplitudes relative to wild type neurons by P19, 2) the GABRA1 epilepsy mutations will increase the relative surface expression of 12-3 subunits in P19 neurons from mutant mice due to an increased 12-3 to 11 subunit ratio, and 3) because 11 subunit expression increases during development, mutant mice will demonstrate more severe epileptic and neurobehavioral phenotypes at P19 than at P12.
The specific aims are: 1) determine the effects of the knock-out and knock-in mutations on total GABAAR expression and IPSC amplitudes throughout development, 2) determine the effects of knock-out and knock-in mutations on expression of 11-5 subunits throughout development and the relationship of 11-5 subunit protein abundance to incorporation in GABAAR and 3) determine the effects of the knock-out and knock-in mutations on the development of the epilepsy and neurobehavioral phenotypes.

Public Health Relevance

Epilepsy is a common neurological disorder that is resistant to medication in one third of the cases. Genetic factors play a role in many forms of epilepsy. The experiments in this proposal will determine the effects of mutations an epilepsy gene and will thus provide crucial information for the development of novel epilepsy therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Stewart, Randall R
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Vanderbilt University Medical Center
Schools of Medicine
United States
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Ding, Li; Gallagher, Martin J (2016) Dynamics of sensorimotor cortex activation during absence and myoclonic seizures in a mouse model of juvenile myoclonic epilepsy. Epilepsia 57:1568-1580
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Arain, Fazal M; Boyd, Kelli L; Gallagher, Martin J (2012) Decreased viability and absence-like epilepsy in mice lacking or deficient in the GABAA receptor ?1 subunit. Epilepsia 53:e161-5