Selective loss of GABAB receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture
Selective loss of GABAB receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture
复制标题
DOI：
10.1073/pnas.0811126106
复制
发表时间：
2009-03-17
影响因子：
11.1
通讯作者：
Sakurai, Takeshi
中科院分区：
文献类型：
--
作者：
Matsuki, Taizo;Nomiyama, Mika;Sakurai, Takeshi
含有神经肽食欲素（hypocretin）的下丘脑神经元在睡眠/觉醒的调节中起重要作用。在这里，我们分析了在体内和体外表型缺乏GABA（B1）基因的小鼠（oxGKO小鼠），特别是在食欲素神经元和证明，GABA（B）受体食欲素神经元是必不可少的稳定和巩固睡眠/觉醒状态。在oxGKO脑切片中，我们发现GABAB受体的缺失降低了食欲素神经元对兴奋性和抑制性输入的敏感性，因为增强的GABA（A）介导的抑制增加了这些神经元中的膜电导并分流了突触后电流。GABA（A）介导的抑制性张力的增加显然是由食欲素受体1型介导的局部GABA能中间神经元的激活引起的，所述中间神经元投射回食欲素神经元。oxGKO小鼠在亮期和暗期都表现出严重的睡眠/觉醒状态片段化，而没有显示出总睡眠时间的异常或昏厥的迹象。因此，食欲素神经元上的GABAB受体在通过睡眠/觉醒状态适当控制食欲素能张力中是至关重要的，从而稳定状态转换机制。
Hypothalamic neurons that contain the neuropeptide orexin (hypocretin) play important roles in the regulation of sleep/wake. Here we analyze the in vivo and in vitro phenotype of mice lacking the GABA(B1) gene specifically in orexin neurons (oxGKO mice) and demonstrate that GABA(B) receptors on orexin neurons are essential in stabilizing and consolidating sleep/wake states. In oxGKO brain slices, we show that the absence of GABAB receptors decreases the sensitivity of orexin neurons to both excitatory and inhibitory inputs because of augmented GABA(A)-mediated inhibition that increases the membrane conductance and shunts postsynaptic currents in these neurons. This increase in GABA(A)-mediated inhibitory tone is apparently the result of an orexin receptor type 1-mediated activation of local GABAergic interneurons that project back onto orexin neurons. oxGKO mice exhibit severe fragmentation of sleep/wake states during both the light and dark periods, without showing an abnormality in total sleep time or signs of cataplexy. Thus, GABAB receptors on orexin neurons are crucial in the appropriate control of the orexinergic tone through sleep/wake states, thereby stabilizing the state switching mechanisms.