Dataset Information

Sex Differences in the Expression of the ?5 Subunit of the GABA_A Receptor in Alcoholics with and without Cirrhosis of the Liver.

ABSTRACT:

Background

Alcohol exposure alters the expression of a large number of genes, resulting in neuronal adaptions and neuronal loss, but the underlying mechanisms are largely unknown. miRNAs are gene repressors that are abundant in the brain. A recent study identified ~ 35 miRNAs that are up-regulated in the prefrontal cortex of human alcoholics and predicted to target genes that are down-regulated in the same region. Although interactions between alcohol-responsive miRNAs and their target genes have been predicted, few studies have validated these predictions.

Methods

We measured the expression of GABA_A ?5 mRNA in the prefrontal and motor cortices of human alcoholics and matched controls using real-time PCR. The expression of miR-203 was measured in a subset of these cases. The predicted interaction of miR-203 and GABRA5 was validated for miR-203 using a luciferase reporter assay.

Results

In both frontal and motor cortices, the expression of GABA_A ?5 was significantly lower in cirrhotic alcoholics compared with controls. Further, the pattern of expression between the groups was significantly different between males and females. The expression of miR-203 was higher in the prefrontal cortex of cirrhotic alcoholics compared with controls and uncomplicated alcoholics. These differences were particularly marked in female cases. Cotransfection of GABRA5 with miR-203 in HEK293T cells reduced luciferase reporter activity.

Conclusion

There are sex differences in the expression of GABA_A ?5 and miR-203 in the brain of human alcoholics which are particularly marked in alcoholics with cirrhosis of the liver. Further, miR-203 may mediate the changes in expression of this GABA_A receptor isoform that is brought about by alcohol exposure.

SUBMITTER: Janeczek P

PROVIDER: S-EPMC7018585 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Sex Differences in the Expression of the α5 Subunit of the GABA<sub>A</sub> Receptor in Alcoholics with and without Cirrhosis of the Liver.

Janeczek Paulina P Colson Natalie N Dodd Peter R PR Lewohl Joanne M JM

Alcoholism, clinical and experimental research 20200109 2

<h4>Background</h4>Alcohol exposure alters the expression of a large number of genes, resulting in neuronal adaptions and neuronal loss, but the underlying mechanisms are largely unknown. miRNAs are gene repressors that are abundant in the brain. A recent study identified ~ 35 miRNAs that are up-regulated in the prefrontal cortex of human alcoholics and predicted to target genes that are down-regulated in the same region. Although interactions between alcohol-responsive miRNAs and their target g ...[more]

PMID: 31840824

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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.

Dataset Information

Sex Differences in the Expression of the ?5 Subunit of the GABA_A Receptor in Alcoholics with and without Cirrhosis of the Liver.

Background

Methods

Results

Conclusion

Publications

Sex Differences in the Expression of the α5 Subunit of the GABA<sub>A</sub> Receptor in Alcoholics with and without Cirrhosis of the Liver.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Sex Differences in the Expression of the ?5 Subunit of the GABAA Receptor in Alcoholics with and without Cirrhosis of the Liver.

Background

Methods

Results

Conclusion

Publications

Sex Differences in the Expression of the α5 Subunit of the GABA<sub>A</sub> Receptor in Alcoholics with and without Cirrhosis of the Liver.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Sex Differences in the Expression of the ?5 Subunit of the GABA_A Receptor in Alcoholics with and without Cirrhosis of the Liver.