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

  • Fritschy J
  • Brünig I
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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 GABAAreceptor expression and function are thought to contribute to prevalent neurological and psychiatric diseases. Molecular cloning and immunochemical characterization of GABAAreceptor subunits revealed a multiplicity of receptor subtypes with specific functional and pharmacological properties. A major tenet of these studies is that GABAAreceptor 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 GABAAreceptor expression and function, focusing on the mechanisms of sorting, targeting, and synaptic clustering of GABAAreceptor 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 GABAAreceptor plasticity, and on alterations of GABAAreceptor expression and localization in major neurological disorders. Altogether, the findings presented in this review underscore the necessity of considering GABAAreceptor-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 GABAAreceptor alterations in disease states and for designing improved therapeutic strategies based on subtype-selective drugs. © 2003 Elsevier Science Inc. All rights reserved.

Author-supplied keywords

  • Benzodiazepine
  • GABAAreceptor
  • Gephyrin
  • Neurosteroid
  • Synaptic clustering
  • Temporal lobe epilepsy

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Authors

  • Jean Marc Fritschy

  • Ina Brünig

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