Kv3 Potassium Channels and Toureete Syndrome

Grant Type
Basic
Grant Year
2007-2008
Institution Location
TX
Institution Organization Name
University of Texas
Investigators Name
Joho, Rolf, PhD

Our laboratory has worked for many years on the physiological role of voltage-gated potassium (Kv) channels in neuronal excitability. Kv channels form a diverse family of ion channels that are involved in regulating the resting membrane potential, the action potential waveform, neurotransmitter release and rhythmic firing patterns of neurons. Among the many different types of Kv channels, members of the Kv3 subfamily (Kv3.1-Kv3.4) display unique biophysical properties that enable neurons to fire narrow actions potentials at very high frequencies. The lack of Kv3 channels leads to broader action potentials, increased neurotransmitter release and, very importantly, impaired high-frequency firing. Kv3.1 channels are expressed in the basal ganglia, a region pivotal in the correct implementation of planned motor activity, that is widely believed to figure prominently in the pathophysiology of Tourette Syndrome. In mutant mice, Kv3.1-deficient neurons show impaired high-frequency firing and the affected animals display a hyperkinetic movement disorder – increased ambulatory and stereotypic activity – reminiscent of basal ganglia dysfunction. It has recently been shown that the distribution of a particular class of neurons – the Kv3.1-expressing, parvalbumin-containing neurons – is significantly altered in several basal ganglia nuclei of individuals with Tourette Syndrome. In the striatum, parvalbumin-containing neurons are the only ones that express Kv3.1 channels, and we expect that these striatal neurons are unable to sustain their characteristic high-frequency firing in the absence of Kv3.1. Given the hypothesized role of basal ganglia dysfunction in Tourette Syndrome and the fact that the distribution of Kv3.1 channel-expressing neurons is altered in basal ganglia nuclei of afflicted individuals, we propose to study these mice as a rodent model of Tourette Syndrome. The work will identify the basal ganglia neurons responsible for the hyperkinetic movement disorder with an initial focus on the striatum. This will enable us to perform electrophysiological studies to understand how the absence of Kv3.1 channels results in striatal dysfunction. In so doing, we will identify molecular targets for novel therapeutics, such as, potentially, Kv3.1 channels themselves. Rolf H. Joho, Ph.D. University of Texas Southwestern Medical Center Dallas, TX Award: $75,000 Tourette Association of America Inc. – Research Grant Award 2007-2008