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GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system


Fritschy, Jean-Marc; Panzanelli, Patrizia (2014). GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system. European Journal of Neuroscience, 39(11):1845-1865.

Abstract

GABAA receptors (GABAA Rs) are ligand-gated Cl(-) channels that mediate most of the fast inhibitory neurotransmission in the central nervous system (CNS). Multiple GABAA R subtypes are assembled from a family of 19 subunit genes, raising the question of the significance of this heterogeneity. In this review, we discuss the evidence that GABAA R subtypes represent distinct receptor populations with a specific spatio-temporal expression pattern in the developing and adult CNS, being endowed with unique functional and pharmacological properties, as well as being differentially regulated at the transcriptional, post-transcriptional and translational levels. GABAA R subtypes are targeted to specific subcellular domains to mediate either synaptic or extrasynaptic transmission, and their action is dynamically regulated by a vast array of molecular mechanisms to adjust the strength of inhibition to the changing needs of neuronal networks. These adaptations involve not only changing the gating or kinetic properties of GABAA Rs, but also modifying the postsynaptic scaffold organised by gephyrin to anchor specific receptor subtypes at postsynaptic sites. The significance of GABAA R heterogeneity is particularly evident during CNS development and adult neurogenesis, with different receptor subtypes fulfilling distinct steps of neuronal differentiation and maturation. Finally, analysis of the specific roles of GABAA R subtypes reveals their involvement in the pathophysiology of major CNS disorders, and opens novel perspectives for therapeutic intervention. In conclusion, GABAA R subtypes represent the substrate of a multifaceted inhibitory neurotransmission system that is dynamically regulated and performs multiple operations, contributing globally to the proper development, function and plasticity of the CNS.

Abstract

GABAA receptors (GABAA Rs) are ligand-gated Cl(-) channels that mediate most of the fast inhibitory neurotransmission in the central nervous system (CNS). Multiple GABAA R subtypes are assembled from a family of 19 subunit genes, raising the question of the significance of this heterogeneity. In this review, we discuss the evidence that GABAA R subtypes represent distinct receptor populations with a specific spatio-temporal expression pattern in the developing and adult CNS, being endowed with unique functional and pharmacological properties, as well as being differentially regulated at the transcriptional, post-transcriptional and translational levels. GABAA R subtypes are targeted to specific subcellular domains to mediate either synaptic or extrasynaptic transmission, and their action is dynamically regulated by a vast array of molecular mechanisms to adjust the strength of inhibition to the changing needs of neuronal networks. These adaptations involve not only changing the gating or kinetic properties of GABAA Rs, but also modifying the postsynaptic scaffold organised by gephyrin to anchor specific receptor subtypes at postsynaptic sites. The significance of GABAA R heterogeneity is particularly evident during CNS development and adult neurogenesis, with different receptor subtypes fulfilling distinct steps of neuronal differentiation and maturation. Finally, analysis of the specific roles of GABAA R subtypes reveals their involvement in the pathophysiology of major CNS disorders, and opens novel perspectives for therapeutic intervention. In conclusion, GABAA R subtypes represent the substrate of a multifaceted inhibitory neurotransmission system that is dynamically regulated and performs multiple operations, contributing globally to the proper development, function and plasticity of the CNS.

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Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:June 2014
Deposited On:13 Feb 2015 13:51
Last Modified:05 Apr 2016 18:51
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0953-816X
Additional Information:This is the accepted version of the following article: European Journal of Neuroscience, Special Issue: EDITORS' ISSUE 2014, Volume 39, Issue 11, pages 1845–1865, June 2014 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/ejn.12534/abstract
Publisher DOI:https://doi.org/10.1111/ejn.12534
PubMed ID:24628861

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