Dataset Information

Postnatal Ethanol Exposure Activates HDAC-Mediated Histone Deacetylation, Impairs Synaptic Plasticity Gene Expression and Behavior in Mice.

ABSTRACT:

Background

Alcohol consumption during pregnancy is widespread and contributes to pediatric neurological defects, including hippocampal and neocortex dysfunction, causing cognitive deficits termed fetal alcohol spectrum disorders. However, the critical mechanisms underlying these brain abnormalities remain poorly described.

Methods

Using a postnatal ethanol exposure (PEE) animal model and pharmacological, epigenetic, synaptic plasticity-related and behavioral approaches, we discovered a novel persistent epigenetic mechanism of neurodegeneration in neonatal hippocampus and neocortex brain regions and of cognitive decline in adult animals.

Results

PEE, which activates caspase-3 (CC3, a neurodegeneration marker), enhanced histone deacetylase (HDAC1-HDAC3) levels and reduced histone 3 (H3) and 4 (H4) acetylation (ac) in mature neurons. PEE repressed the expression of several synaptic plasticity genes, such as brain-derived neurotrophic factor, C-Fos, early growth response 1 (Egr1), and activity-regulated cytoskeleton-associated protein (Arc). Detailed studies on Egr1 and Arc expression revealed HDAC enrichment at their promoter regions. HDAC inhibition with trichostatin A (TSA) before PEE rescued H3ac/H4ac levels and prevented CC3 formation. Antagonism/null mutation of cannabinoid receptor type-1 (CB1R) before PEE to inhibit CC3 production prevented Egr1 and Arc loss via epigenetic events. TSA administration before PEE prevented postnatal ethanol-induced loss of Egr1 and Arc expression and neurobehavioral defects in adult mice via epigenetic remodeling. In adult mice, 3-day TSA administration attenuated PEE-induced behavioral defects.

Conclusions

These findings demonstrate that CB1R/HDAC-mediated epigenetic remodeling disrupts gene expression and is a critical step in fetal alcohol spectrum disorder-associated cognitive decline but is reversed by restoration of histone acetylation in the brain.

SUBMITTER: Shivakumar M

PROVIDER: S-EPMC7251635 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Postnatal Ethanol Exposure Activates HDAC-Mediated Histone Deacetylation, Impairs Synaptic Plasticity Gene Expression and Behavior in Mice.

Shivakumar Madhu M Subbanna Shivakumar S Joshi Vikram V Basavarajappa Balapal S BS

The international journal of neuropsychopharmacology 20200501 5

<h4>Background</h4>Alcohol consumption during pregnancy is widespread and contributes to pediatric neurological defects, including hippocampal and neocortex dysfunction, causing cognitive deficits termed fetal alcohol spectrum disorders. However, the critical mechanisms underlying these brain abnormalities remain poorly described.<h4>Methods</h4>Using a postnatal ethanol exposure (PEE) animal model and pharmacological, epigenetic, synaptic plasticity-related and behavioral approaches, we discove ...[more]

PMID: 32170298

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Project description:Jaundice is one of the most common problems encountered in newborn infants, due to immaturity of hepatic conjugation and transport processes for bilirubin. Although the majority of neonatal jaundice is benign, some neonates with severe hyperbilirubinemia develop bilirubin encephalopathy or kernicterus. Accumulation of unconjugated bilirubin (UCB) in selected brain regions may result in temporary or permanent impairments of auditory, motor, or cognitive function; however, the molecular mechanisms by which UCB elicits such neurotoxicity are still poorly understood. The present study is undertaken to investigate whether prolonged exposure of rat organotypic hippocampal slice cultures to UCB alters the induction of long-term synaptic plasticity.Using electrophysiological recording techniques, we find that exposure of hippocampal slice cultures to clinically relevant concentrations of UCB for 24 or 48 h results in an impairment of CA1 long-term potentiation (LTP) and long-term depression (LTD) induction in a time- and concentration-dependent manner. Hippocampal slice cultures stimulated with UCB show no changes in the secretion profiles of the pro-inflammatory cytokines, interleukin-1beta and tumor necrosis factor-alpha, or the propidium ioide uptake. UCB treatment produced a significant decrease in the levels of NR1, NR2A and NR2B subunits of N-methyl-D-aspartate (NMDA) receptors through a calpain-mediated proteolytic cleavage mechanism. Pretreatment of the hippocampal slice cultures with NMDA receptor antagonist or calpain inhibitors effectively prevented the UCB-induced impairment of LTP and LTD.Our results indicate that the proteolytic cleavage of NMDA receptor subunits by calpain may play a critical role in mediating the UCB-induced impairment of long-term synaptic plasticity in the hippocampus. These observations provide new insights into the molecular mechanisms underlying UCB-induced impairment of hippocampal synaptic plasticity which, in turn, might provide opportunities for the development of novel therapeutic strategies that targets these pathways for treatment.

Dataset Information

Postnatal Ethanol Exposure Activates HDAC-Mediated Histone Deacetylation, Impairs Synaptic Plasticity Gene Expression and Behavior in Mice.

Background

Methods

Results

Conclusions

Publications

Postnatal Ethanol Exposure Activates HDAC-Mediated Histone Deacetylation, Impairs Synaptic Plasticity Gene Expression and Behavior in Mice.

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