title: Thalamic δ-subunit containing GABAA receptors promote electrocortical signatures of deep non-REM sleep but do not mediate the effects of etomidate at the thalamus in vivo.
abstract: Extrasynaptic δ-subunits containing GABAA receptors (δGABAARs) are sensitive targets for several commonly used hypnotic agents and mediate tonic neuronal inhibition. δGABAARs are highly expressed within the thalamus and their activation promotes a switch from tonic to burst firing in vitro. Here we test two hypotheses in vivo. (1) Activation of thalamic δGABAARs will elicit electrocortical signatures consistent with widespread thalamocortical burst firing such as increased delta oscillations (1-4 Hz) and reciprocal changes in spindle-like oscillations (7-14 Hz). (2) These signatures will be recapitulated by the general anesthetic etomidate, if the electrocortical effects of etomidate at the thalamus are mediated by δGABAARs. Microperfusion of the δGABAAR-preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; 10 and 50 μM) into the ventrobasal complex produced significant effects on electrocortical activity in wild-type mice, but not in mice lacking δGABAARs (Gabrd(-/-)), i.e., the effects with THIP were dependent on δGABAARs. THIP (1) increased 1-4 Hz power in wakefulness and nonrapid-eye movement (NREM) sleep; (2) reduced spindle-like oscillations in NREM sleep; and (3) increased the speed of stable transitions into NREM sleep, indicating effects on state-space dynamics. In contrast, microperfusion of etomidate (10 and 30 μM) into the ventrobasal complex produced effects on electrocortical activity that were independent of δGABAARs, i.e., effects occurred in wild-type and Gabrd(-/-) mice. Etomidate (1) decreased 1-4 Hz power, increased 8-12 Hz, and/or 12-30 Hz power in all sleep-wake states; (2) increased spindle-like oscillations; and (3) increased REM sleep expression. These results indicate that thalamic δGABAARs promote electrocortical signatures of deep NREM sleep, but do not mediate the effects of etomidate at the thalamus in vivo.
authors.affiliation: Departments of Medicine.
authors.forename: Lia
authors.initials: L
authors.lastname: Mesbah-Oskui
authors.affiliation: Physiology, and Anesthesia, University of Toronto, Toronto, Ontario, M5S 1A8, Canada, and Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario, M4N 3M5, Canada.
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
authors.affiliation: Departments of Medicine, Physiology, and richard.horner@utoronto.ca.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Horner
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology*; D005045:Etomidate / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism*; D012894:Sleep Stages / Q000187:drug effects / Q000502:physiology*; D013788:Thalamus / Q000187:drug effects / Q000502:physiology*
chemical_list: D006993:Hypnotics and Sedatives; D021122:Protein Subunits; D011963:Receptors, GABA-A; D005045:Etomidate
keywords: anesthesia; extrasynaptic GABAA receptors; sleep; thalamus