Abstract

The neuronal circuits mediating the sedative action of diazepam are unknown. Although the motor-depressant action of diazepam is suppressed in α1(H101R) homozygous knockin mice expressing diazepam-insensitive α1-GABA_A receptors, global α1-knockout mice show greater motor sedation with diazepam. To clarify this paradox, attributed to compensatory up-regulation of the α2 and α3 subunits, and to further identify the neuronal circuits supporting diazepam-induced sedation, we generated Emx1-cre-recombinase-mediated conditional mutant mice, selectively lacking the α1 subunit (forebrain-specific α1^-/-) or expressing either a single wild-type (H) or a single point-mutated (R) α1 allele (forebrain-specific α1^-/H and α1^-/R mice, respectively) in forebrain glutamatergic neurons. In the rest of the brain, α1^-/R mutants are heterozygous α1(H101R) mice. Forebrain-specific α1^-/- mice showed enhanced diazepam-induced motor depression and increased expression of the α2 and α3 subunits in the neocortex and hippocampus, in comparison with their pseudo-wild-type littermates. Forebrain-specific α1^-/R mice were less sensitive than α1^-/H mice to the motor-depressing action of diazepam, but each of these conditional mutants had a similar behavioral response as their corresponding control littermates. Unexpectedly, expression of the α1 subunit was reduced in forebrain, notably in α1^-/R mice, and the α3 subunit was up-regulated in neocortex, indicating that proper α1 subunit expression requires both alleles. In conclusion, conditional manipulation of GABA_A receptor α1 subunit expression can induce compensatory changes in the affected areas. Specifically, alterations in GABA_A receptor expression restricted to forebrain glutamatergic neurons reproduce the behavioral effects seen after a global alteration, thereby implicating these neurons in the motor-sedative effect of diazepam.