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Role of GABAA receptors in cognition.

Abstract：

: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 gamma-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 alpha(2)-GABA(A) receptors. Neurons expressing alpha(3)-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 alpha(5)-GABA(A) receptors. Chronic pathological pain was under the regulation of spinal and cortical alpha(2)- (and alpha(3)-) 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 alpha(2)/alpha(3)-GABA(A) receptor ligand.

journal_name

Biochem Soc Trans

journal_title

Biochemical Society transactions

authors

Möhler H

doi

10.1042/BST0371328

subject

Has Abstract

pub_date

2009-12-01 00:00:00

pages

1328-33

issue

Pt 6

eissn

0300-5127

issn

1470-8752

pii

BST0371328

journal_volume

pub_type

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Role of GABAA receptors in cognition.