Role of Kv3 Potassium Channels in Arousal-State Dynamics

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DESCRIPTION (provided by applicant): 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. Subunits for Kv3.1 and Kv3.3 channels are expressed in several brain regions known to be involved in the regulation the sleep-wake cycle and of motor activity. When the function of one or both of these genes is genetically eliminated, mutant mice display Kv3-null allele-dependent changes that include severe sleep loss, due to unstable slow-wave sleep, and constitutive hyperactivity. To understand how the altered electrical properties of neuronal subpopulations located in distinct brain areas cause the observed behavioral alterations, we propose to selectively suppress Kv3 activity in subsets of neurons in WT mice. Cell-specific ablation of Kv3 activity will be achieved using recombinant adeno-associated virus encoding a dominant-negative Kv3.1 channel subunit. Brain region-specific suppression of Kv3 activity in combination with brain-slice recordings and behavioral tests will enable us to correlate altered neuronal firing patterns in distinct neuronal subpopulations with the correspondingly altered sleep-wake behavior. Hence, Kv3 mutant mice will serve as well-defined models to study the pathophysiology of hyperactivity and sleep dysfunction. We have developed potassium channel-mutant mice that serve as well-defined rodent models to study the electrophysiological changes in particular brain regions that cause constitutive hyperactivity and dysfunctional sleep-wake patterns due to unstable sleep.