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Intricacies of GABA_A Receptor Function: The Critical Role of the ?3 Subunit in Norm and Pathology.

ABSTRACT: Neuronal intracellular chloride ([Cl^-]_i) is a key determinant in ?-aminobutyric acid type A (GABA)ergic signaling. ?-Aminobutyric acid type A receptors (GABA_ARs) mediate both inhibitory and excitatory neurotransmission, as the passive fluxes of Cl^- and HCO₃^- via pores can be reversed by changes in the transmembrane concentration gradient of Cl^-. The cation-chloride co-transporters (CCCs) are the primary systems for maintaining [Cl^-]_i homeostasis. However, despite extensive electrophysiological data obtained in vitro that are supported by a wide range of molecular biological studies on the expression patterns and properties of CCCs, the presence of ontogenetic changes in [Cl^-]_i-along with the consequent shift in GABA reversal potential-remain a subject of debate. Recent studies showed that the ?3 subunit possesses properties of the P-type ATPase that participates in the ATP-consuming movement of Cl^- via the receptor. Moreover, row studies have demonstrated that the ?3 subunit is a key player in GABA_AR performance and in the appearance of serious neurological disorders. In this review, we discuss the properties and driving forces of CCCs and Cl^-, HCO₃^-ATPase in the maintenance of [Cl^-]_i homeostasis after changes in upcoming GABA_AR function. Moreover, we discuss the contribution of the ?3 subunit in the manifestation of epilepsy, autism, and other syndromes.

SUBMITTER: Menzikov SA

PROVIDER: S-EPMC7867123 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Intricacies of GABAA Receptor Function: The Critical Role of the β3 Subunit in Norm and Pathology.

Menzikov Sergey A SA Morozov Sergey G SG Kubatiev Aslan A AA

International journal of molecular sciences 20210201 3

Neuronal intracellular chloride ([Cl-]i) is a key determinant in γ-aminobutyric acid type A (GABA)ergic signaling. γ-Aminobutyric acid type A receptors (GABAARs) mediate both inhibitory and excitatory neurotransmission, as the passive fluxes of Cl- and HCO3- via pores can be reversed by changes in the transmembrane concentration gradient of Cl-. The cation-chloride co-transporters (CCCs) are the primary systems for main ...[more]

PMID: 33535681

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Project description:Rationale: Current first-line treatments for stress-related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "?5-PAM"), a positive allosteric modulator selective for ?5-subunit containing GABAA receptors found predominantly on cortical pyramidal cell dendrites, has anti-stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with ?5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic ?5-PAM treatments produce a pattern of decreased stress-induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic ?5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to ?5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with ?5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of ?5 subunit-containing GABAA receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.

Project description:BackgroundDisruption of normal brain development is implicated in numerous psychiatric disorders with neurodevelopmental origins, including autism spectrum disorder (ASD). Widespread abnormalities in brain structure and functions caused by dysregulations of neurodevelopmental processes has been recently shown to exert adverse effects across generations. An imbalance between excitatory/inhibitory (E/I) transmission is the putative hypothesis of ASD pathogenesis, supporting by the specific implications of inhibitory γ-aminobutyric acid (GABA)ergic system in autistic individuals and animal models of ASD. However, the contribution of GABAergic system in the neuropathophysiology across generations of ASD is still unknown. Here, we uncover profound alterations in the expression and function of GABAA receptors (GABAARs) in the amygdala across generations of the VPA-induced animal model of ASD.MethodsThe F2 generation was produced by mating an F1 VPA-induced male offspring with naïve females after a single injection of VPA on embryonic day (E12.5) in F0. Autism-like behaviors were assessed by animal behavior tests. Expression and functional properties of GABAARs and related proteins were examined by using western blotting and electrophysiological techniques.ResultsSocial deficit, repetitive behavior, and emotional comorbidities were demonstrated across two generations of the VPA-induced offspring. Decreased synaptic GABAAR and gephyrin levels, and inhibitory transmission were found in the amygdala from two generations of the VPA-induced offspring with greater reductions in the F2 generation. Weaker association of gephyrin with GABAAR was shown in the F2 generation than the F1 generation. Moreover, dysregulated NMDA-induced enhancements of gephyrin and GABAAR at the synapse in the VPA-induced offspring was worsened in the F2 generation than the F1 generation. Elevated glutamatergic modifications were additionally shown across generations of the VPA-induced offspring without generation difference.ConclusionsTaken together, these findings revealed the E/I synaptic abnormalities in the amygdala from two generations of the VPA-induced offspring with GABAergic deteriorations in the F2 generation, suggesting a potential therapeutic role of the GABAergic system to generational pathophysiology of ASD.

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Intricacies of GABA_A Receptor Function: The Critical Role of the ?3 Subunit in Norm and Pathology.

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Intricacies of GABA<sub>A</sub> Receptor Function: The Critical Role of the β3 Subunit in Norm and Pathology.

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Dataset Information

Intricacies of GABAA Receptor Function: The Critical Role of the ?3 Subunit in Norm and Pathology.

Publications

Intricacies of GABA<sub>A</sub> Receptor Function: The Critical Role of the β3 Subunit in Norm and Pathology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Intricacies of GABA_A Receptor Function: The Critical Role of the ?3 Subunit in Norm and Pathology.