Matsuki Taizo, Nomiyama Mika, Takahira Hitomi, Hirashima Noriko, Kunita Satoshi, Takahashi Satoru, Yagami Ken-ichi, Kilduff Thomas S, Bettler Bernhard, Yanagisawa Masashi, Sakurai Takeshi
Yanagisawa Orphan Receptor Project, ERATO, Japan Science and Technology Agency, Saitama 322-0012 Japan.
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4459-64. doi: 10.1073/pnas.0811126106. Epub 2009 Feb 25.
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 GABA(B) 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, GABA(B) receptors on orexin neurons are crucial in the appropriate control of the orexinergic tone through sleep/wake states, thereby stabilizing the state switching mechanisms.
含有神经肽食欲素（下丘脑分泌素）的下丘脑神经元在睡眠/觉醒调节中发挥重要作用。在此，我们分析了特异性缺失食欲素神经元中GABA(B1)基因的小鼠（oxGKO小鼠）的体内和体外表型，并证明食欲素神经元上的GABA(B)受体对于稳定和巩固睡眠/觉醒状态至关重要。在oxGKO脑片中，我们发现GABA(B)受体缺失会降低食欲素神经元对兴奋性和抑制性输入的敏感性，这是因为增强的GABA(A)介导的抑制增加了膜电导并分流了这些神经元中的突触后电流。GABA(A)介导的抑制性张力增加显然是食欲素1型受体介导的局部GABA能中间神经元激活的结果，这些中间神经元会投射回食欲素神经元。oxGKO小鼠在光照期和黑暗期均表现出睡眠/觉醒状态的严重碎片化，总睡眠时间无异常，也无猝倒迹象。因此，食欲素神经元上的GABA(B)受体对于通过睡眠/觉醒状态适当控制食欲素能张力至关重要，从而稳定状态转换机制。
