Research Grant Award

James Maylie, PhD

Oregon Health & Science University, Portland, OR
Molecular and Cellular Physiology of Episodic Ataxia Type 1, EA1

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder in which affected individuals experience attacks of imbalance and uncontrolled movements, often associated with jerking or tremor of the head and arms and asynchronous twitching of muscle fibers within the facial and hand muscles. Genetic linkage studies and DNA sequence analysis have identified mutations in KCNA1, the gene encoding the voltagegated potassium channel, Kv1.1, as underlying EA1. Potassium channels are important contributors to the geneses and modulation of electrical activity in every cell particular in the central nervous system. Most affected individuals respond favorably to treatment with acetazolamide, a carbonic anhydrase inhibitor, that reduces the frequency of attacks. The basis for benefit provided by acetazolamide is not understood and one goal of this application is to provide an understanding of the cellular mechanism by which acetazolamide works, as well as provide an animal model to test other potential treatments. The classic neurological concept that the cerebellum is a site of motor control originates from clinical observations that patients with cerebellar damage often exhibit motorrelated symptoms of gait ataxia, dysmetria, hypotonia, and tremor. The Kv1.1 gene is expressed in interneurons of cerebellum the release the neurotransmitter GABA, the major inhibitory transmitter in the brain, but not in Purkinje cells, the primary cells that project information out from the cerebellum. It is therefore likely that EA1 symptoms results from altered GABA release. To understand the cellular and behavioral mechanisms that result in EA1, we have constructed a transgenic mouse model for EA1. We will use the EA1 mouse model for behavioral, electrophysiological, and calcium imaging investigations. These experiments will comprise an exemplary use of a diverse technical repertoire and integrated approaches to understand an inherited human disorder in an ion channel gene. The EA1 mice may also suggest and also serve for testing future therapeutic approaches.