Kv2.2: A Novel Molecular Target to Study the Role of Basal Forebrain GABAergic Neurons in the Sleep-Wake Cycle
Kv2.2: A Novel Molecular Target to Study the Role of Basal Forebrain GABAergic Neurons in the Sleep-Wake Cycle
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DOI：
10.5665/sleep.3212
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发表时间：
2013-12-01
期刊：
影响因子：
5.6
通讯作者：
Misonou, Hiroaki
中科院分区：
文献类型：
--
作者：
Hermanstyne, Tracey O.;Subedi, Kalpana;Misonou, Hiroaki
研究目的：基底前脑(BF)被认为是调节动物睡眠-觉醒周期的重要脑区。伽马氨基丁酸(GABA)能神经元是该区域最主要的神经元群体。然而，由于缺乏特定的分子工具，BF-GABA能神经元的作用尚未完全阐明。以前，我们已经在BF的Broca斜角带的大细胞视前区和水平支上发现了大约60%的GABA能神经元上Kv2.2电压门控钾通道的高表达，因此我们建议将其作为研究这一神经元群体的潜在分子靶点。在这项研究中，我们试图确定Kv2.2表达的神经元在睡眠-觉醒周期调节中的功能作用。设计：睡眠剥夺前后两种基因型之间以及每种基因型内部的睡眠分析。背景：动物睡眠研究实验室。参与者：成年小鼠。以C57/BL6为背景的野生型和Kv2.2基因敲除小鼠。干预：记录基础状态和轻度兴奋诱导的睡眠剥夺6h后的EEG/EMG。结果：免疫组织化学染色显示，这些表达Kv2.2的神经元似乎在觉醒状态下优先激活。因此，我们利用Kv2.2缺陷小鼠测试了BF中表达Kv2.2的神经元是否参与了觉醒。BF GABA能神经元c-Fos表达增强。这些基因敲除的小鼠比野生型小鼠表现出更长的清醒时间，而且睡眠不足进一步加剧了这种表型。此外，对其皮层脑电的深入分析显示，在非快速眼动睡眠状态下，其Delta频率活动显著降低。结论：这些结果揭示了Kv2.2表达的神经元在睡眠-觉醒周期调节中的意义。
Study Objectives: The basal forebrain (BF) has been implicated as an important brain region that regulates the sleep-wake cycle of animals. Gamma-aminobutyric acidergic (GABAergic) neurons are the most predominant neuronal population within this region. However, due to the lack of specific molecular tools, the roles of the BF GABAergic neurons have not been fully elucidated. Previously, we have found high expression levels of the Kv2.2 voltage-gated potassium channel on approximately 60% of GABAergic neurons in the magnocellular preoptic area and horizontal limb of the diagonal band of Broca of the BF and therefore proposed it as a potential molecular target to study this neuronal population. In this study, we sought to determine the functional roles of the Kv2.2-expressing neurons in the regulation of the sleep-wake cycle.Design: Sleep analysis between two genotypes and within each genotype before and after sleep deprivation.Setting: Animal sleep research laboratory.Participants: Adult mice. Wild-type and Kv2.2 knockout mice with C57/BL6 background.Interventions: EEG/EMG recordings from the basal state and after sleep-deprivation which was induced by mild aggitation for 6 h.Results: Immunostaining of a marker of neuronal activity indicates that these Kv2.2-expressing neurons appear to be preferentially active during the wake state. Therefore, we tested whether Kv2.2-expressing neurons in the BF are involved in arousal using Kv2.2-deficient mice. BF GABAergic neurons exhibited augmented expression of c-Fos. These knockout mice exhibited longer consolidated wake bouts than wild-type littermates, and that phenotype was further exacerbated by sleep deprivation. Moreover, in-depth analyses of their cortical electroencephalogram revealed a significant decrease in the delta-frequency activity during the nonrapid eye movement sleep state.Conclusions: These results revealed the significance of Kv2.2-expressing neurons in the regulation of the sleep-wake cycle.