Analysis of GABAA 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 (alpha1, alpha5, alpha6, beta2, beta3, gamma2, delta, and rho1) and (b) knockin mice that carry point mutations affecting the action of modulatory drugs [alpha1(H101R), alpha2(H101R), alpha3(H126R), alpha5(H105R), and,beta3(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.