Associate editor: A.L. Morrow
Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications

https://doi.org/10.1016/S0163-7258(03)00037-8Get rights and content

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.

Introduction

As the main inhibitory neurotransmitter in the vertebrate CNS, γ-aminobutyric acid (GABA) modulates every aspect of brain function. On the molecular level, the action of GABA is mediated by ionotropic (GABAA) (Barnard et al., 1998) and metabotropic (GABAB) (Bowery et al., 2002) receptors, which are ubiquitously expressed, possibly on every single neuron in the CNS. GABAergic function is fine-tuned at multiple levels (Cherubini & Conti, 2001), including transmitter synthesis by two isoforms of glutamic acid decarboxylase (GAD) Erlander et al., 1991, Esclapez et al., 1994, Soghomonian & Martin, 1998; vesicular storage Dumoulin et al., 1999, Gasnier, 2000; Ca2+-dependent and independent release Wall & Usowicz, 1997, Vautrin et al., 2000, Kirischuk et al., 2002; re-uptake in neurons and glial cells Borden, 1996, Quick et al., 1997; and activation of multiple receptors, localized pre-, post-, and extrasynaptically. All these components are not only molecularly heterogeneous, but they also are regulated both at the transcriptional and post-transcriptional level, allowing for an extremely complex array of interactions at the molecular, cellular, and systemic level. The significance of GABAergic transmission is underscored by the multiple neurological and psychiatric diseases for which an alteration in the GABAergic system has been postulated (Mohler, 2000), including epilepsy Duncan, 1999, Olsen et al., 1999, Coulter, 2001, anxiety disorders (Malizia, 1999), ethanol dependence (Morrow et al., 2001), Huntington's disease (Kunig et al., 2000), Angelman syndrome (DeLorey et al., 1998), and schizophrenia Lewis, 2000, Nutt & Malizia, 2001, Blum & Mann, 2002. In particular, GABAA receptors represent a major site of action for clinically important drugs, including benzodiazepines, barbiturates, and some general anesthetics, as well as drugs of abuse such as ethanol Sieghart, 1995, Grobin et al., 1998, Dilger, 2002, Mohler et al., 2002.

The purpose of this review is to highlight recent advances pertaining to the regulation of GABAA receptor expression and function, with a focus on the mechanisms of synapse formation and postsynaptic clustering of GABAA receptors, on dynamic changes of receptor localization and function, on interactions with endogenous modulators, and on alterations associated with major neurological diseases. The selected topics highlight emerging concepts that challenge commonly held views about the establishment, maintenance, and function of GABAergic synapses in the healthy and diseased brain. In particular, it is becoming evident that the number of GABAA receptors available for synaptic transmission is regulated both on a short- and a long-term basis, and that their functional properties can be adjusted very rapidly in response to numerous stimuli. Much of this progress stems from the discovery and characterization during the 1990s of the molecular heterogeneity of GABAA receptors. These studies demonstrated the existence of multiple subtypes of GABAA receptors with differential function, pharmacology, and regulation. These aspects will be reviewed in the next section to highlight the importance of this concept before discussing regulatory mechanisms in the following sections.

Section snippets

Identification and neuron-specific expression of GABAA receptor subtypes

GABAA receptors belong to the superfamily of ligand-gated ion channels Unwin, 1993, Barnard, 2001. Along with glycine receptors, they mediate fast inhibitory neurotransmission in the vertebrate CNS by gating Cl ions through an integral membrane channel. GABAA receptors form multimeric complexes assembled from a family of at least 21 constituent subunits (α1–6, β1–4, γ1–4, δ, ρ1–3, θ, π) Barnard et al., 1998, Whiting, 1999. The molecular heterogeneity of GABAA receptors is much larger than that

Trafficking and clustering of postsynaptic GABAA receptors

Synapses are highly specialized subcellular compartments containing a vast array of proteins that are required presynaptically for transmitter synthesis, storage, release, and re-uptake, and postsynaptically for signal reception and transduction. A probably even larger number of proteins provide a structural scaffold ensuring appropriate assembly, location, and function of the pre- and postsynaptic specializations. For instance, an ensemble of ∼70 proteins has been identified in the

Regulation of GABAA receptor expression by neurosteroids: physiological and pathophysiological implications

A major group of endogenous modulators of GABAA receptors that is gaining considerable interest are the neurosteroids, and in particular, the metabolites of progesterone and of deoxycorticosterone, which appear to regulate important physiological functions and pathophysiological states through a direct, non-genomic interaction with specific GABAA receptor subtypes. Indeed, neuroactive steroids, such as allopregnanolone (3α-hydroxy-5α-pregnan-20-one) or allotetrahydrodeoxycorticosterone

Alterations of GABAA receptor expression and function in neurological and psychiatric disorders

The investigation of the cellular mechanisms regulating GABAA receptor expression and function (Section 3) revealed three principal findings: (1) that the neuron- and synapse-specific expression of GABAA receptor subtypes is largely cell-autonomous (Brünig et al., 2002a); (2) that clustering of GABAA receptors at postsynaptic sites and the maintenance of GABAA receptor clusters depends on distinct mechanisms Levi et al., 1999, Levi et al., 2002, Brünig et al., 2002b, Garin et al., 2002; and (3)

Conclusions and outlook

The remarkable progress in our knowledge of GABAergic synaptic transmission opens novel horizons and challenges classical views about the formation, maintenance, and function of GABAergic synapses in the healthy and diseased brain. These findings 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. In our opinion, four major novel

Acknowledgements

Our work was supported by the Swiss National Science Foundation (Grants Nr. 31-52869.97 and 31-63901.00 and NCCR Neural Plasticity and Repair). We are grateful to Corinne Sidler for excellent technical support and Verena Dünki for secretarial assistance.

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    Present address: Friedrich-Miescher-Institute, CH-4058 Basel, Switzerland.

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