Direct activation of G-protein-gated inward rectifying K+ channels promotes nonrapid eye movement sleep
| Autor: | Zhiwei Guan, Kui Xiao, Xinmin Simon Xie, Julian Xie, Jidong Fang, Jingxi Zhang, C. David Weaver, Bende Zou, Conrado Pascual, William S. Cao, Craig W. Lindsley, Frank Kayser, James Xie |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Patch-Clamp Techniques Action Potentials Basic Science of Sleep and Circadian Rhythms Mice Transgenic Inhibitory postsynaptic potential Hippocampus Non-rapid eye movement sleep Mice 03 medical and health sciences chemistry.chemical_compound Organ Culture Techniques 0302 clinical medicine Postsynaptic potential Physiology (medical) Animals G protein-coupled inwardly-rectifying potassium channel Neurons Electromyography Chemistry Phenylurea Compounds Membrane hyperpolarization Orexin Mice Inbred C57BL Baclofen G Protein-Coupled Inwardly-Rectifying Potassium Channels nervous system 030228 respiratory system Excitatory postsynaptic potential Pyrazoles Female Sleep Stages Neurology (clinical) Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Sleep. 42 |
| ISSN: | 1550-9109 0161-8105 |
| DOI: | 10.1093/sleep/zsy244 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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