Abstract
Primary electroencephalographic (EEG) features of sleep arise in part from thalamocortical neural assemblies, and cortical potassium channels have long been thought to play a critical role. We have exploited the regionally dynamic nature of sleep EEG to develop a novel screening strategy and used it to conduct an adeno-associated virus (AAV)-mediated RNAi screen for cellular roles of 31 different voltage-gated potassium channels in modulating cortical EEG features across the circadian sleep-wake cycle. Surprisingly, a majority of channels modified only electroencephalographic frequency bands characteristic of sleep, sometimes diurnally or even in specific vigilance states. Confirming our screen for one channel, we show that depletion of the KCa1.1 (or "BK") channel reduces EEG power in slow-wave sleep by slowing neuronal repolarization. Strikingly, this reduction completely abolishes transcriptomic changes between sleep and wake. Thus, our data establish an unexpected connection between transcription and EEG power controlled by specific potassiumchannels. We postulate that additive dynamic roles of individual potassium channels could integrate different influences upon sleep and wake within single neurons.
Highlights
Beyond its evident behavioral manifestations, sleep is characterized by widespread synchronized electroencephalographic oscillations of defined frequency: theta (4–8 Hz) during rapid eye movement sleep (REM-S) and delta and ‘‘slow waves’’ during non-REM sleep (NREM-S) [1]
An associated virus (AAV)-Mediated RNAi Screen for Cortical Ion Channels Important to Sleep EEG For the current study, we developed an AAV that expressed an short hairpin RNA (shRNA) under control of the neuron-specific CAG promoter, as well as a tRFP fluorescent marker
Injection of shRNA-containing virus locally into one parietal cortex and injection of control virus expressing a scrambled hairpin into the same location contralaterally resulted in viral cassette expression locally within maximally 1 mm3 of cortex after several days
Summary
Beyond its evident behavioral manifestations, sleep is characterized by widespread synchronized electroencephalographic oscillations of defined frequency: theta (4–8 Hz) during rapid eye movement sleep (REM-S) and delta and ‘‘slow waves’’ (less than 4 Hz) during non-REM sleep (NREM-S) [1]. Slowwave oscillations during NREM-S, comprised of the summed electrical potentials of the underlying brain cells, vary markedly in local fashion [2,3,4]. They are thought to arise primarily (but probably not exclusively) from communication across thalamus and neocortex [5]. Their amount and power are proportional to time and quality of waking experience, fostering hypotheses about their recuperative roles for synaptic homeostasis [6], brain metabolism [7,8,9], and cellular stress [10, 11]. A widely cited theoretical framework for understanding sleep is the ‘‘two-process model’’ of sleep regulation by circadian and homeostatic factors [14]
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