Direct activation of G-protein-gated inward rectifying K + channels promotes nonrapid eye movement sleep

Bende Zou, William S. Cao, Zhiwei Guan, Kui Xiao, Conrado Pascual, Julian Xie, Jingxi Zhang, James Xie, Frank Kayser, Craig W. Lindsley, C. David Weaver, Jidong Fang, Xinmin Simon Xie

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Abstract

Study Objectives A major challenge in treating insomnia is to find effective medicines with fewer side effects. Activation of G-protein-gated inward rectifying K + channels (GIRKs) by GABA B agonists baclofen or γ-hydroxybutyric acid (GHB) promotes nonrapid eye movement (NREM) sleep and consolidates sleep. However, baclofen has poor brain penetration, GHB possesses abuse liability, and in rodents both drugs cause spike-wave discharges (SWDs), an absence seizure activity. We tested the hypothesis that direct GIRK activation promotes sleep without inducing SWD using ML297, a potent and selective GIRK activator. Methods Whole-cell patch-clamp recordings from hypocretin/orexin or hippocampal neurons in mouse brain slices were made to study neuronal excitability and synaptic activity; spontaneous activity, locomotion, contextual and tone-conditioned memory, and novel object recognition were assessed. Electroencephalogram/electromyogram (EEG/EMG) recordings were used to study GIRK modulation of sleep. Results ML297, like baclofen, caused membrane hyperpolarization, decreased input resistance, and blockade of spontaneous action potentials. Unlike baclofen, ML297 (5-10 μM) did not cause significant depression of postsynaptic excitatory and inhibitory currents (EPSCs-IPSCs), indicating preferential postsynaptic inhibition. ML297 (30 mg/kg, i.p.) inhibited wake activity and locomotion, and preferentially increased NREM sleep without altering EEG delta power, REM sleep, inducing SWDs, or impairing conditioned memory and novel object recognition. Conclusions This study finds that direct activation of neuronal GIRK channels modulates postsynaptic membrane excitability and prolongs NREM sleep without changing sleep intensity, inducing SWDs, or impairing memory in rodents. These results suggest that direct GIRK activation with a selective compound may present an innovative approach for the treatment of chronic insomnia.

Original languageEnglish (US)
Article numberzsy244
JournalSleep
Volume42
Issue number3
DOIs
StatePublished - Mar 19 2019

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All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Physiology (medical)

Cite this

Zou, B., Cao, W. S., Guan, Z., Xiao, K., Pascual, C., Xie, J., Zhang, J., Xie, J., Kayser, F., Lindsley, C. W., Weaver, C. D., Fang, J., & Xie, X. S. (2019). Direct activation of G-protein-gated inward rectifying K + channels promotes nonrapid eye movement sleep. Sleep, 42(3), [zsy244]. https://doi.org/10.1093/sleep/zsy244