Voltage-gated potassium (Kv) channels form a large and 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. Their pivotal role is highlighted by several inherited human diseases caused by mutations in Kv channel genes. Among the many different types of Kv channels, Kv3-type channels display unique biophysical properties: very rapid activation and deactivation kinetics, high thresholds of activation and large unit conductances, properties that enable neurons to fire narrow actions potentials at extremely high frequencies. Among Kv3-type channels, subunits for Kv3.1 and Kv3.3 are highly expressed in the cerebellum, and some of the behaviorally observed phenotypes in Kv3-null mutant mice are characteristic of cerebellar dysfunction such as impaired motor performance and, of relevance to this proposal, very high alcohol sensitivity. We have previously shown that altered firing patterns of cerebellar Purkinje cells are responsible for impaired motor function yet not for heightened alcohol sensitivity. Here, we propose experiments to test the hypothesis that the extreme alcohol sensitivity of Kv3.1/Kv3.3-double mutants originates from changes in granule cell physiology, neurons that normally express high levels of Kv3.1 and Kv3.3 channel subunits. We will use a molecular biological approach to localize the neuronal origin of high alcohol sensitivity in the cerebellum of Kv3-mutant mice. In future work, this approach will enable us to study the altered neuronal physiology in brain-slice preparations and to correlate changes in neuronal firing patterns with the corresponding behavioral alterations, in particular with the intoxicating effects of alcohol.
We have recently developed potassium channel-mutant mice that are very sensitive to low concentrations of alcohol. Hence, these mice will serve as well-defined rodent models to study the electrophysiological changes, i.e., altered neuronal firing patterns, that cause extreme alcohol sensitivity.
