Formation and plasticity of GABAergic synapses: Physiological mechanisms and pathophysiological implications

Abstract

γ-Aminobutyric acidA (GABAA) receptors mediate most of the fast inhibitory neurotransmission in the CNS. They represent a major site of action for clinically relevant drugs, such as benzodiazepines and ethanol, and endogenous modulators, including neuroactive steroids. Alterations in GABAA receptor expression and function are thought to contribute to prevalent neurological and psychiatric diseases. Molecular cloning and immunochemical characterization of GABAA receptor subunits revealed a multiplicity of receptor subtypes with specific functional and pharmacological properties. A major tenet of these studies is that GABAA receptor heterogeneity represents a key factor for fine-tuning of inhibitory transmission under physiological and pathophysiological conditions. The aim of this review is to highlight recent findings on the regulation of GABAA receptor expression and function, focusing on the mechanisms of sorting, targeting, and synaptic clustering of GABAA receptor subtypes and their associated proteins, on trafficking of cell-surface receptors as a means of regulating synaptic (and extrasynaptic) transmission on a short-time basis, on the role of endogenous neurosteroids for GABAA receptor plasticity, and on alterations of GABAA receptor expression and localization in major neurological disorders. Altogether, the findings presented in this review underscore the necessity of considering GABAA receptor-mediated neurotransmission as a dynamic and highly flexible process controlled by multiple mechanisms operating at the molecular, cellular, and systemic level. Furthermore, the selected topics highlight the relevance of concepts derived from experimental studies for understanding GABAA receptor alterations in disease states and for designing improved therapeutic strategies based on subtype-selective drugs. © 2003 Elsevier Science Inc. All rights reserved.