Isoflurane is a potent modulator of extrasynaptic GABA_A receptors in the thalamus

Volatile anesthetics are used clinically to produce analgesia, amnesia, unconsciousness, blunted autonomic responsiveness, and immobility. Previous work has shown that the volatile anesthetic isoflurane, at concentrations that produce unconsciousness (250-500 μM), enhances fast synaptic inhibition in the brain mediated by GABA_A receptors (GABA_A-Rs). In addition, isoflurane causes sedation at concentrations lower than those required to produce unconsciousness or analgesia. In this study, we found that isoflurane, at low concentrations (25-85 μM) associated with its sedative actions, elicits a sustained current associated with a conductance increase in thalamocortical neurons in the mouse ventrobasal (VB) nucleus. These isoflurane-evoked currents reversed polarity close to the Cl^- equilibrium potential and were totally blocked by the GABA_A-R antagonist gabazine. Isoflurane (25-250 μM) produced no sustained current in VB neurons from GABA_A-R α₄-subunit knockout (Gabra4^-/-) mice, although 250 μM isoflurane enhanced synaptic inhibition in VB neurons from both wild-type and Gabra4^-/- mice. These data indicate an obligatory requirement for α₄-subunit expression in the generation of the isoflurane-activated current. In addition, isoflurane directly activated α₄β₂δ GABA_A-Rs expressed in human embryonic kidney 293 cells, and it was more potent at α₄β₂δ than at α₁β₂γ₂ receptors (the presumptive extrasynaptic and synaptic GABA_A-R subtypes in VB neurons). We conclude that the extrasynaptic GABA_A-Rs of thalamocortical neurons are sensitive to low concentrations of isoflurane. In view of the crucial role of the thalamus in sensory processing, sleep, and cognition, the modulation of these extrasynaptic GABA_A-Rs by isoflurane may contribute to the sedation and hypnosis associated with low doses of this anesthetic agent.