Analysis of GABA Receptor Assembly and Function in Targeted Mutant Mice

Abstract

GABA is the major inhibitory neurotransmitter in the central nervous system, acting via ionotropic GABAA receptors and metabotropic GABAB receptors. GABAA receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions and the enhancement of GABAA receptor-mediated fast synaptic inhibition is the basis of the pharmacotherapy of various neurological and psychiatric disorders. The GABAB receptor is a target for the treatment of spasticity, migraine headache and musculoskeletal pain. GABAA receptors are pentameric complexes assembled from a repertoire of at least 18 subunits (α1-oα6, β1-β3,γ1-γδ∈,o,ρ1-σ3), whereas GABAB receptors are heterodimers composed of the GABAB1 and GABAB2 subunits. Two kinds of GABAA receptor-targeted mutant mice have been generated: (1) knock-out mice which lack individual GABAA receptor subunits (α1, α5, α6, β2, β3, γ2, δ, ρ1) and (2) knock-in mice which carry point mutations affecting the action of modulatory drugs [α1(H101R), α2(H101R), α3(H126R) and α5(H105R)]. With regard to the GABAB receptor, the GABAB1 receptor subunit has been knocked out. Whereas the knockout mice have provided information primarily with respect to regulation of subunit gene transcription, receptor assembly and some physiological functions of individual receptor subtypes, the point-mutated knock-in mice, in which specific GABAA receptor subtypes are insensitive to diazepam, have revealed the contribution of individual receptor subtypes to the broad pharmacological spectrum of diazepam. The insights obtained studying targeting mutant mice are expected to aid in the development of novel subtype-specific drugs with fewer side effects than the drugs currently in clinical use.