Presynaptic muscarinic-nicotinic modulation of GABAergic inputs to neurons in the REM sleep executive area of the rostral pons.

A large body of evidence indicates that cholinergic neurons in the brainstem tegmental nuclei play a pivotal role in controlling neurons of the reticular nucleus pontis oralis (PnO), an area considered executive for rapid eye movement (REM) sleep onset and maintenance. More recent data indicate that the PnO is also under GABAergic control-which gates REM sleep-thereby highlighting the importance of interactions between cholinergic and GABAergic processes as a key mechanism in REM sleep regulation. Here, we used a rat mesopontine slice preparation to investigate the modulation of GABAergic inputs to PnO neurons by cholinergic agents. Carbachol, a mixed muscarinic-nicotinic cholinergic agonist, provoked either depression or facilitation of single monosynaptic GABAergic inhibitory postsynaptic currents (IPSCs) evoked by extracellular stimulation of the region of mesopontine tegmental nuclei. Both effects were presynaptic in origin and are likely attributable to the activation of distinct presynaptic cholinergic receptors, as depression was replicated by muscarine (presynaptic inhibition) and facilitation by nicotine (presynaptic facilitation). Furthermore, IPSCs evoked by stimulation patterns mimicking physiological activity (short trains at 15 Hz) were also affected by cholinergic agonists. Muscarine caused presynaptic inhibition accompanied by frequency facilitation and nicotine promoted the opposite effect. Notably, both agonists converge toward reducing net inhibitory charge transfer during physiologically relevant patterns of presynaptic activity. This suggests a potential additional mechanism by which cholinergic modulation may relieve GABAergic inhibition of PnO neurons under physiological conditions, possibly contributing as a local component of the reciprocal inhibitory interactions between sleep-regulating networks in REM sleep brainstem executive areas.NEW & NOTEWORTHY Despite extensive research on brainstem sleep mechanisms, GABAergic-cholinergic interactions regulating rapid eye movement (REM) sleep gating and ultradian timing remain elusive. We show presynaptic muscarinic and nicotinic control of GABAergic terminals in the pontine reticular nucleus (PnO), a key region for REM sleep initiation and maintenance. Our data suggest that cholinergic signaling may relieve GABAergic inhibition of PnO neurons as part of a mutual inhibitory mechanism between REM-controlling circuits. This interaction could sharpen transitions into REM sleep.