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

We generated mice with a selective loss of GABAB receptors in orexin neurons. Orexin neurons in these GABAB1-/-(orexin) mice showed reduced responsiveness to GABAA receptor agonists due to a compensatory increase in GABAA receptor-mediated inhibition. This increased GABAA receptor-mediated inhibition of orexin neurons is due to orexin-1 receptor-mediated activation of local GABAergic interneurons. Surprisingly, orexin neurons were also less responsive to glutamate, apparently because the augmented GABAA receptor-mediated inhibition increases the membrane conductance and shunts excitatory currents. These observations indicate that absence of GABAB receptors decreases the sensitivity of orexin neurons to both excitatory and inhibitory inputs. GABAB1-/-(orexin)mice exhibited severe fragmentation of sleep/wake states during both the light and dark periods without affecting total sleep time or inducing cataplexy, indicating that GABAB receptors are crucial regulators of orexin neurons and that "fine tuning" of orexin neurons by inhibitory and excitatory inputs is important for the stability of sleep/waking states.