Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons

Abstract

Hawryluk JM, Ferrari LL, Keating SA, Arrigoni E. Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons. J Neurophysiol 107: 2769 -2781, 2012. First published February 22, 2012 doi:10.1152/jn.00528.2011.-Adenosine has been proposed as an endogenous homeostatic sleep factor that accumulates during waking and inhibits wake-active neurons to promote sleep. It has been specifically hypothesized that adenosine decreases wakefulness and promotes sleep recovery by directly inhibiting wake-active neurons of the basal forebrain (BF), particularly BF cholinergic neurons. We previously showed that adenosine directly inhibits BF cholinergic neurons. Here, we investigated 1) how adenosine modulates glutamatergic input to BF cholinergic neurons and 2) how adenosine uptake and adenosine metabolism are involved in regulating extracellular levels of adenosine. Our experiments were conducted using whole cell patch-clamp recordings in mouse brain slices. We found that in BF cholinergic neurons, adenosine reduced the amplitude of AMPAmediated evoked glutamatergic excitatory postsynaptic currents (EPSCs) and decreased the frequency of spontaneous and miniature EPSCs through presynaptic A 1 receptors. Thus we have demonstrated that in addition to directly inhibiting BF cholinergic neurons, adenosine depresses excitatory inputs to these neurons. It is therefore possible that both direct and indirect inhibition may synergistically contribute to the sleep-promoting effects of adenosine in the BF. We also found that blocking the influx of adenosine through the equilibrative nucleoside transporters or inhibiting adenosine kinase and adenosine deaminase increased endogenous adenosine inhibitory tone, suggesting a possible mechanism through which adenosine extracellular levels in the basal forebrain are regulated. magnocellular preoptic nucleus; substantia innominata; adenosine A 1 receptors; electrophysiology; excitatory postsynaptic currents; in vitro; mice IN THE LAST EIGHTY YEARS, a large number of studies have been directed toward identifying the endogenous sleep factors that could build during the waking period to drive the need for sleep and then be dissipated by sleep itself (Achermann

The menagerie of the basal forebrain: how many (neural) species are there, what do they look like, how do they behave and who talks to whom?

“…Specific lesions of cholinergic neurons expressing the p75 neurotrophin receptor abolished increases in sleep and EEG delta power following sleep deprivation [44,46]. In addition, increases in the inhibitory neuromodulator, adenosine [47,48], during prolonged wakefulness [49] were blocked by cholinergic lesions [46]. …”

“…sleep deprivation) there is accumulation of extracellular adenosine due to direct release from neurons as well as breakdown from the neurotransmitter/gliotransmitter, ATP. Adenosine inhibits BF cholinergic and GABAergic projection neurons by inhibiting their glutamatergic inputs via A1 receptors [47,48], thereby promoting a homeostatic sleep response. Activation of a subset of GABAergic neurons containing somatostatin may facilitate spontaneous transitions into non-REM sleep by direct postsynaptic inhibition of wake-promoting cholinergic and GABAergic neurons.…”

Intrinsic membrane properties and cholinergic modulation of mouse basal forebrain glutamatergic neurons in vitro

“…When compared to mouse cholinergic neurons (Hedrick and Waters, 2010; Hawryluk et al, 2012; McKenna et al, 2013), vGluT2+ neurons were much smaller, had narrower action potentials, smaller afterhyperpolarizations and had a much higher maximal firing frequency (56 Hz for vGluT2+ vs 14 Hz for cholinergic; (McKenna et al, 2013)). BF vGluT2+ neurons exhibited time-dependent inward rectification mediated by activation of HCN channels whereas cholinergic neurons exhibit a different type of rectification mediated by potassium channels (Hedrick and Waters, 2010; Hawryluk et al, 2012; McKenna et al, 2013). A small subset of BF vGluT2+ neurons exhibited an unusual pattern of cluster firing we have not observed in BF cholinergic or GABAergic neurons.…”

Disrupted sleep–wake regulation in type 1 equilibrative nucleoside transporter knockout mice

“…Similar measurements of spontaneous sleep-wake dependent changes in [AD] ex in mice could not be achieved due to short durations of sleep-wake episodes that yield insufficient volumes of microdialysates. [AD] ex , via its action on the presynaptic A1 adenosine receptors, inhibits glutamatergic input within BF area consisting of cortically projecting wake active neurons, resulting in sleep induction (Hawryluk et al, 2012, Yang et al, 2013). However, our observation that a low dose of AD (100μM) perfusion into BF resulted in increased NRδ KO mice to match the WT littermates suggests that an optimal level of [AD] ex is critical for increased quality of sleep.…”