GABA-ergic modulation of pontine cholinergic and noradrenergic neurons for REM sleep generation

Abstract

The mechanism of generation of rapid eye movement sleep (REMS) has been intensely studied since its discovery in cat and rat models. Since then, the neuropharmacological as well as electrophysiological studies have brought out the prominent role played by the noradrenergic (NA-ergic) neurons in locus coeruleus (LC) and cholinergic neurons in laterodorsal/pedunculopontine tegmentum (LDT/PPT) in REMS generation. The NA-ergic neurons cease firing during REMS, and are known as REM-OFF neurons, whereas cholinergic neurons increase their firing rate during REMS, and are known as REM-ON neurons. The interaction between NA-ergic LC neurons and the cholinergic LDT/PPT neurons has long been postulated as a central mechanism of REMS generation. Interestingly, LC and LDT/PPT have a large number of GABA-ergic neurons and also receive GABA-ergic afferents from other brain areas. Studies from our as well as other sleep laboratories have provided the evidence indicating that GABA plays a critical neuromodulatory role in the interaction between pontine NA-ergic and cholinergic systems. On the basis of the studies done in our laboratory, it was proposed that the cholinergic projections from LDT/PPT into LC excite GABA-ergic neurons to release GABA, which inhibit the LC NA-ergic neurons to increase REMS. In PPT, GABA acts on the NA-ergic axonal terminals from LC to inhibit the release of noradrenaline (NA), thereby disinhibiting the cholinergic REM-ON neurons and increasing REMS. Further, we have shown that the increase in intracerebral NA as a consequence of noncessation of LC NA-ergic neurons (as during REMS deprivation) increases Na-K ATPase activity. The increased Na-K ATPase activity affects the membrane excitability, which along with physiological/morphological changes induced by elevated NA may contribute to the pathology associated with REMS related disorders.