Selective loss of GABA B receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture
- 17 March 2009
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (11), 4459-4464
- https://doi.org/10.1073/pnas.0811126106
Abstract
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 GABAB1 gene specifically in orexin neurons (oxGKO mice) and demonstrate that GABAB 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 GABAA-mediated inhibition that increases the membrane conductance and shunts postsynaptic currents in these neurons. This increase in GABAA-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.This publication has 36 references indexed in Scilit:
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