Selective loss of GABAB receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture
摘要：
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.
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DOI：
10.1073/pnas.0811126106
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年份：
2009
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