Received for publication November 26, 2007.
Revised December 18, 2007.
Accepted for publication December 18, 2007.

Isoflurane is a Potent Modulator of Extrasynaptic GABA_A Receptors in the Thalamus

Abstract

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 (250-500µM), 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 µM-85 µM) associated with its sedative actions, elicits a tonic current associated with a conductance increase in thalamocortical neurons in the mouse ventrobasal (VB) nucleus. These isoflurane-induced currents reversed polarity at the Cl^- equilibrium potential and were totally blocked by the GABA_A-R antagonist gabazine. Isoflurane (25 µM-250 µM) produced no tonic current in VB neurons from GABA_A-R ₄ 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 ₄ subunit expression in the generation of the isoflurane-induced tonic current. In addition, isoflurane directly activated ₄₂ GABA_A-Rs expressed in HEK293 cells, and was more potent at ₄₂ than at ₁₂₂ 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.

Key words: Extrasynaptic, GABAA receptor, Isoflurane, Tonic inhibition, alpha-4 subunit, ion channel

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