Nearly half of all epilepsies have an important genetic component, therefore the identification and modeling of mutations that cause epilepsy may provide important insights into mechanisms and treatment. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the first and only, idiopathic epilepsy for which specific mutations in a single gene have been identified. There is evidence that this disease is caused by the dysfunction of a nicotinic acetylcholine receptor subunit, alpha4. An insertion mutation in the alpha4 receptor channel reduces its permeability to calcium, which may alter a critical function of these receptors in the brain: modulation of neurotransmitter release. The objective of this research proposal is to create a genetic (knockin) animal model of ADNFLE using recent innovative applications of gene knockout technology. Animals ill be analyzed for the epilepsy phenotype. Incorporation of a reporter in both wild type and mutant alpha4 targeting constructs will allow a visual reporter in both wild type and mutant alpha4 targeting constructs will allow a visual identification of neurons that contain normal and mutant alpha4 receptors. The function of mutant alpha4 receptors will be assessed electrophysiologically in cultured hippocampal neurons.
