Activation of basal forebrain purinergic P2 receptors promotes wakefulness in mice

Abstract

The functions of purinergic P2 receptors (P2Rs) for extracellular adenosine triphosphate (ATP) are poorly understood. Here, for the first time, we show that activation of P2Rs in an important arousal region, the basal forebrain (BF), promotes wakefulness, whereas inhibition of P2Rs promotes sleep. Infusion of a non-hydrolysable P2R agonist, ATP-γ-S, into mouse BF increased wakefulness following sleep deprivation. ATP-γ-S depolarized BF cholinergic and cortically-projecting GABAergic neurons in vitro, an effect blocked by antagonists of ionotropic P2Rs (P2XRs) or glutamate receptors. In vivo, ATP-γ-S infusion increased BF glutamate release. Thus, activation of BF P2XRs promotes glutamate release and excitation of wake-active neurons. Conversely, pharmacological antagonism of BF P2XRs decreased spontaneous wakefulness during the dark (active) period. Together with previous findings, our results suggest sleep-wake regulation by BF extracellular ATP involves a balance between excitatory, wakefulness-promoting effects mediated by direct activation of P2XRs and inhibitory, sleep-promoting effects mediated by degradation to adenosine.

Activation of basal forebrain astrocytes induces wakefulness without compensatory changes in sleep drive

“…The ATP metabolite adenosine via A1 receptors can inhibit neurons or excite neurons via disinhibition (via GABAergic interneurons) [17,[56][57][58]. Direct activation of BF purinergic receptors has also been shown to profoundly alter sleep and wake architecture [59]. Therefore, local release of astroglial ATP might be expected to have complex effects on BF neurons.…”

Basal forebrain parvalbumin neurons modulate vigilant attention and rescue deficits produced by sleep deprivation

“…SD by gentle handling was conducted using previously validated and widely used procedures, such as adding new objects into the cages and a gentle touch of the animals by a brush when mice were attempting to sleep. The effectiveness of these procedures in producing near continuous wakefulness was previously validated using concurrent EEG/EMG recordings (Yang et al, 2018).…”

Translational approaches to influence sleep and arousal

“…However, ATP also activates a large family of ionotropic (P2X) and metabotropic purinergic receptors (P2Y) located on neurons, glia, blood vessels and immune cells. Activation of P2 receptors in the basal forebrain promotes wakefulness via excitatory effects on cholinergic and cortically projecting GABAergic neurons ( Yang et al, 2018 ), whereas activation of P2X 7 receptors promotes sleep ( Krueger et al, 2010 ), possibly by actions on glia in the cortex, which as discussed in Section 4 are emerging as important regulators of sleep.…”