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

Abstract

We generated mice with a selective loss of GABAB receptors in orexin neurons. Orexin neurons in these GABAB1^-/-(orexin) mice showed reduced responsiveness to GABA_A receptor agonists due to a compensatory increase in GABAA receptor-mediated inhibition. This increased GABA_A 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 GABA_A receptor-mediated inhibition increases the membrane conductance and shunts excitatory currents. These observations indicate that absence of GABA_B 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 GABA_B 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.