Abstract
The modulation of neuronal cell firing is mediated by the release of the neurotransmitter GABA (γ-aminobuytric acid), which binds to two major families of receptors. The ionotropic GABAA receptors (GABAARs) are composed of five distinct subunits that vary in expression by brain region and cell type. The action of GABA on GABAARs is modulated by a variety of clinically and pharmacologically important drugs such as benzodiazepines and alcohol. Exposure to and abuse of these substances disrupts homeostasis and induces plasticity in GABAergic neurotransmission, often via the regulation of receptor expression. Here, we review the regulation of GABAAR subunit expression in adaptive and pathological plasticity, with a focus on substance use. We examine the factors influencing the expression of GABAAR subunit genes including the regulation of the 5′ and 3′ untranslated regions, variations in DNA methylation, immediate early genes and transcription factors that regulate subunit expression, translational and post-translational modifications, and other forms of receptor regulation beyond expression. Advancing our understanding of the factors regulating GABAAR subunit expression during adaptive plasticity, as well as during substance use and withdrawal will provide insight into the role of GABAergic signaling in substance use disorders, and contribute to the development of novel targeted therapies.
Highlights
Neuronal firing patterns in the brain are powerfully modulated by the inhibitory neurotransmitter γ-aminobutyric acid (GABA)
Many of the above described factors such as cAMP response element-binding protein (CREB), early growth response protein (Egr) family members, and methyl CpG-binding protein 2 (MeCP2) have been implicated in the response to substance use, studies have not yet examined how these factors may regulate GABAA receptors (GABAARs) expression in the maladaptive plasticity that contributes to the development of substance use disorder
GABAARs are highly specialized receptors comprised of a variety of subunits that vary in expression based on their location and function [2,3]
Summary
Neuronal firing patterns in the brain are powerfully modulated by the inhibitory neurotransmitter γ-aminobutyric acid (GABA). GABAAR subunit expression is temporally regulated, with the expression of GABAAR subunit α2, α3, α5, and β3 mRNA predominating during early development, which are superseded by α1, α4, β2 and δ subunit mRNAs in the adult brain [4] These changes coincide with the switch in the reversal potential for chloride, transitioning GABA from being depolarizing to hyperpolarizing [4,5]. GABAergic signaling at the cellular level is often modulated by changes in the expression of GABAARs. GABAAR gene expression is temporally regulated throughout development and the life span, as well as in response to experience, substance use, and as a result of a number of neuropathologies [4,21,22]. We will discuss what is known about the regulation of GABAAR expression across the levels in both normal and pathological states, with a focus on substance use and withdrawal
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