How and why we sleep are central unsolved questions in medicine. Nearly 40 million people in the United States are estimated to experience chronic or intermittent sleep disorders such as narcolepsy, sleep apnea, restless leg syndrome and insomnia. Traditional approaches have identified several neuronal populations whose interplay is important in generating sleep and wakefulness. How that interplay is established, how it is altered and its cellular and molecular consequences, remain poorly understood. The long-term objective of this proposal is to determine the molecular identity and function of ion channels and receptors expressed by sleep-related neurons in order to understand the molecular mechanisms controlling sleep generation. This application focuses on the identity and function of a family of K+ channels subunit genes in controlling activity of mesopontine cholinergic neurons which are believed to play a pivotal role in the generation of wakefulness and REM sleep. Our central hypothesis is that K+ channels formed by Kv3 subunits regulate action potential shape, intracellular Ca2+ levels, repetitive firing and the release of transmitter from mesopontine cholinergic neurons. To test this hypothesis we will use pharmacological methods with whole-cell patch clamp recordings in brain slices from wild-type and Kv3 knock-out mice. The results of these studies will 1) identify and verify the intrinsic electrophysiological properties of important REM-sleep related neurons in mouse; 2) determine the molecular identity and function of native K+ channels formed by Kv3 subunits; 3) elucidate new mechanisms controlling the activity and release of transmitter by REM sleep-related neurons; 4) identify novel functions of Kv3 channels which have previously been associated with the fast-spiking phenotype rather than broad-spiking phenotype of brainstem cholinergic neurons. These results will contribute to our understanding of the molecular basis of sleep regulation as well as advancing the mouse as a platform for future sleep research.
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