Selective loss of GABA_B receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture

Hypothalamic neurons that contain the neuropeptide orexin (hypo- cretin) 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.