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-GABAA 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 litter-mates. 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 GABAA receptor α1 subunit expression can induce compensatory changes in the affected areas. Specifically, alterations in GABAA 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.
ASJC Scopus subject areas
- Molecular Medicine