Analysis of GABA_A Receptor Function and Dissection of the Pharmacology of Benzodiazepines and General Anesthetics Through Mouse Genetics

GABA_A receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity, and memory functions, and the enhancement of GABA_A receptor-mediated fast synaptic inhibition is the basis for the pharmacotherapy of various neurological and psychiatric disorders. Two kinds of GABA_A receptor-targeted mutant mice have been generated: (a) knockout mice that lack individual GABA_A receptor subunits (α1, α5, α6, β2, β3, γ2, δ, and ρ1) and (b) knockin mice that carry point mutations affecting the action of modulatory drugs [α1(H101R), α2(H101R), α3(H126R), α5(H105R), and β3(N265M)]. Whereas the knockout mice have provided information primarily with respect to the regulation of subunit gene transcription, receptor assembly, and some physiological functions of individual receptor subtypes, the point-mutated knockin mice in which specific GABA_A receptor subtypes are insensitive to diazepam or some general anesthetics have revealed the specific contribution of individual receptor subtypes to the pharmacological spectrum of diazepam and general anesthetics.