GABAA receptors involved in sleep and anaesthesia: β1- versus β3-containing assemblies

Abstract

The histaminergic neurons of the posterior hypothalamus (tuberomamillary nucleus-TMN) control wakefulness, and their silencing through activation of GABA(A) receptors (GABA(A)R) induces sleep and is thought to mediate sedation under propofol anaesthesia. We have previously shown that the β1 subunit preferring fragrant dioxane derivatives (FDD) are highly potent modulators of GABA(A)R in TMN neurons. In recombinant receptors containing the β3N265M subunit, FDD action is abolished and GABA potency is reduced. Using rat, wild-type and β3N265M mice, FDD and propofol, we explored the relative contributions of β1- and β3-containing GABA(A)R to synaptic transmission from the GABAergic sleep-on ventrolateral preoptic area neurons to TMN. In β3N265M mice, GABA potency remained unchanged in TMN neurons, but it was decreased in cultured posterior hypothalamic neurons with impaired modulation of GABA(A)R by propofol. Spontaneous and evoked GABAergic synaptic currents (IPSC) showed β1-type pharmacology, with the same effects achieved by 3 μM propofol and 10 μM PI24513. Propofol and the FDD PI24513 suppressed neuronal firing in the majority of neurons at 5 and 100 μM, and in all cells at 10 and 250 μM, respectively. FDD given systemically in mice induced sedation but not anaesthesia. Propofol-induced currents were abolished (1-6 μM) or significantly reduced (12 μM) in β3N265M mice, whereas gating and modulation of GABA(A)R by PI24513 as well as modulation by propofol were unchanged. In conclusion, β1-containing (FDD-sensitive) GABA(A)R represent the major receptor pool in TMN neurons responding to GABA, while β3-containing (FDD-insensitive) receptors are gated by low micromolar doses of propofol. Thus, sleep and anaesthesia depend on different GABA(A)R types.

Neonatal Propofol and Etomidate Exposure Enhance Inhibitory Synaptic Transmission in Hippocampal Cornus Ammonis 1 Pyramidal Neurons

“…[1123] Propofol mediates α5-containing GABA A R, which is found at extrasynapses and co-assembled with β3-containing GABA A R, which contributes to the “tail” kinetics of synaptic currents. [2425] A previous study showed that the α5 GABA A receptor subunit can be assembled into synapses later during development and is responsible for the generation of a slow current. [26] However, GABA tonic alteration after neonatal propofol exposure was not explored in this study and might need further study.…”

α4βδ GABA A receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)

“…To date, only few such compounds have been reported (35,36). The preference for β1 may, in part, explain the sleepmediating effects of GHB, because the endogenous pathway of sleep has been shown to depend mainly on β1-containing GABA A receptors, whereas anesthesia and hypnosis are mediated through β3-containing receptors (37,38). β1 is associated with extrasynaptic receptors (39) and abundantly found in the hippocampus and cortex (40), where high-affinity GHB binding sites are predominantly located (6).…”

Proton- and ammonium-sensing by histaminergic neurons controlling wakefulness

“…Cell-attached recording was used to register action potential currents (Perkins, 2006). Visual identification of histaminergic neurons was confirmed at the end of experiments by application of the histamine 3 (H3) receptor agonist R-α-methylhistamine (0.2 μM) (Yanovsky et al, 2012) (in mM): KCl 130, NaCl 10, MgCl 2 2, CaCl 2 0.25, glucose 5, Hepes 5, Mg-ATP 5, EGTA 10, Na-GTP 0.3, pH 7.3 adjusted with 1 M KOH. Temperature was held at 33 ± 0.5° if not mentioned otherwise.…”