Genetic reduction of GABA_A receptor γ2 subunit expression potentiates the immobilizing action of isoflurane

Potentiation of inhibitory γ-aminobutyric acid subtype A (GABA_A) receptor function is involved in the mechanisms of anesthetic action. The present study examined the immobilizing action of the volatile anesthetic isoflurane in mice with double knockout (DKO) of phospholipase C-related inactive protein (PRIP)-1 and -2. Both of these proteins play important roles in the expression of GABA_A receptors containing the γ2 subunit on the neuronal cell surface. Immunohistochemistry for GABA_A receptor subunits demonstrated reduced expression of γ2 subunits in the spinal cord of the DKO mice. Immunohistochemistry also revealed up-regulation of the α1 and β3 subunits even though there were no apparent differences in the immunoreactivities for the β2 subunits between wild-type and DKO mice. The tail-clamp method was used to evaluate the anesthetic/immobilizing effect of isoflurane and the minimum alveolar concentration (MAC) was significantly lower in DKO mice compared with wild-type controls (1.07 ± 0.01% versus 1.36 ± 0.04% atm), indicating an increased sensitivity to isoflurane in DKO mice. These immunohistochemical and pharmacological findings suggest that reduced expression of the GABA_A receptor γ2 subunit affects the composition and function of spinal GABA_A receptors and potentiates the immobilizing action of isoflurane.