Role of GABA_A receptors in cognition

Complex brains have developed specialized mechanisms for the grouping of principal cells into temporal coalitions of local or distant networks: the inhibitory interneuron ‘clocking’ networks. They consist of GABAergic (where GABA is γ-aminobutyric acid) interneurons of a rich diversity. In cortical circuits, these neurons control spike timing of the principal cells, sculpt neuronal rhythms, select cell assemblies and implement brain states. On the basis of these considerations, the deficits in cognition, emotion and perception in psychiatric disorders such as anxiety, depression or schizophrenia are considered to manifest themselves through a dysregulation of the inhibitory interneuron ‘clocking’ network as a final common denominator, irrespective of the diverse underlying disease pathologies. The diversity of GABAergic interneurons is paralleled by a corresponding diversity of GABA_A receptors in network regulation. The region-, cell- and domain-specific location of these receptor subtypes offers the possibility to gain functional insights into the role of behaviourally relevant neuronal circuits. Using genetic manipulation, the regulation of anxiety behaviour was attributed to neuronal circuits characterized by the expression of α₂-GABA_A receptors. Neurons expressing α₃-GABA_A receptors, located mainly in aminergic and basal forebrain cholinergic neurons, were related to a hyperdopaminergic phenotype, typical of schizophrenic symptoms. Temporal and spatial memory were selectively modulated by extrasynaptic α₅-GABA_A receptors. Chronic pathological pain was under the regulation of spinal and cortical α₂- (and α₃-) GABA_A receptors. Thus the relevance of the diversity of inhibitory GABA_A receptor subtypes for the regulation of cognition, emotion and memory is increasingly being recognized. The clinical proof-of-concept of a subtype-specific pharmacology is most advanced for the alleviation of cognitive dysfunctions in schizophrenia, based on the treatment of patients with an α₂/α₃-GABA_A receptor ligand.