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Histone deacetylases mediate GABAA receptor expression, physiology, and behavioral maladaptations in rat models of alcohol dependence.

ABSTRACT: Alcohol use disorders are chronic debilitating diseases characterized by severe withdrawal symptoms that contribute to morbidity and relapse. GABAA receptor (GABAAR) adaptations have long been implicated in the chronic effects of alcohol and contribute to many withdrawal symptoms associated with alcohol dependence. In rodents, GABAAR hypofunction results from decreases in Gabra1 expression, although the underlying mechanism controlling Gabra1 expression after chronic ethanol exposure is still unknown. We found that chronic ethanol exposure using either ethanol gavage or two-bottle choice voluntary access paradigms decreased Gabra1 expression and increased Hdac2 and Hdac3 expression. Administration of the HDAC inhibitor trichostatin A (TSA) after chronic ethanol exposure prevents the decrease in Gabra1 expression and function as well as the increase in Hdac2 and Hdac3 expression in both the cortex and the medial prefrontal cortex (mPFC). Chronic ethanol exposure and withdrawal, but not acute ethanol exposure or acute withdrawal, cause a selective upregulation of HDAC2 and HDAC3 associated with the Gabra1 promoter that accompanies a decrease in H3 acetylation of the Gabra1 promoter and the reduction in GABAAR ?1 subunit expression. TSA administration prevented each of these molecular events as well as behavioral manifestations of ethanol dependence, including tolerance to zolpidem-induced loss of righting reflex, reduced open-arm time in the elevated plus maze, reduced center-time and locomotor activity in the open-field assay, and TSA reduced voluntary ethanol consumption. The results show how chronic ethanol exposure regulates the highly prominent GABAAR ?1 subunit by an epigenetic mechanism that represents a potential treatment modality for alcohol dependence.

SUBMITTER: Bohnsack JP

PROVIDER: S-EPMC5983537 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Histone deacetylases mediate GABAA receptor expression, physiology, and behavioral maladaptations in rat models of alcohol dependence.

Bohnsack John Peyton JP Hughes Benjamin A BA O'Buckley Todd K TK Edokpolor Kamyra K Besheer Joyce J Morrow A Leslie AL

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20180227 7

Alcohol use disorders are chronic debilitating diseases characterized by severe withdrawal symptoms that contribute to morbidity and relapse. GABAA receptor (GABAAR) adaptations have long been implicated in the chronic effects of alcohol and contribute to many withdrawal symptoms associated with alcohol dependence. In rodents, GABAAR hypofunction results from decreases in Gabra1 expression, although the underlying mechanism controlling Gabra1 expression after chr ...[more]

PMID: 29520058

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Project description:Epigenetic mechanisms like altered histone acetylation may have a crucial role in epileptogenesis. In two mouse models of temporal lobe epilepsy, we investigated changes in the expression of class II histone deacetylases (HDAC), a group of signal transducers that shuttle between nucleus and cytoplasm. Intrahippocampal injection of kainic acid (KA) induced a status epilepticus, development of spontaneous seizures (after 3 days), and finally chronic epilepsy and granule cell dispersion. Expression of class II HDAC mRNAs was investigated at different time intervals after KA injection in the granule cell layers and in sectors CA1 and CA3 contralateral to the site of KA injection lacking neurodegeneration. Increased expression of HDAC5 and 9 mRNAs coincided with pronounced granule cell dispersion in the KA-injected hippocampus at late intervals (14-28 days after KA) and equally affected both HDAC9 splice variants. In contrast, in the pilocarpine model (showing no granule cell dispersion), we observed decreases in the expression of HDAC5 and 9 at the same time intervals. Beyond this, striking similarities between both temporal lobe epilepsy models such as fast decreases in HDAC7 and 10 mRNAs during the acute status epilepticus were observed, notably also in the contralateral hippocampus not affected by neurodegeneration. The particular patterns of HDAC mRNA expression suggest a role in epileptogenesis and granule cell dispersion. Reduced expression of HDACs may result in increased expression of pro- and anticonvulsive proteins. On the other hand, export of HDACs from the nucleus into the cytoplasm could allow for deacetylation of cytoplasmatic proteins involved in axonal and dendritic remodeling, like granule cell dispersion. HDAC 5 and HDAC 9 expression is highly increased in granule cells of the KA-injected hippocampus and parallels granule cell dispersion. Both HDACs are thought to be targeted to the cytoplasm and to act there by deacetylating cytoplasmatic (e.g. cytosceleton-related) proteins.

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Histone deacetylases mediate GABAA receptor expression, physiology, and behavioral maladaptations in rat models of alcohol dependence.

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Histone deacetylases mediate GABA<sub>A</sub> receptor expression, physiology, and behavioral maladaptations in rat models of alcohol dependence.

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