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Published on: July 13, 2014
Postnatal Ethanol Exposure Activates HDAC-Mediated Histone Deacetylation, Impairs Synaptic Plasticity Gene Expression
Madhu Shivakumar1, Shivakumar Subbanna1, Vikram Joshi1
1Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York.
Insights
Fetal alcohol spectrum disorders cause cognitive deficits by altering brain gene expression. Restoring histone acetylation reversed these alcohol-induced neurodevelopmental and cognitive defects in a mouse model.
Area of Science:
- Neuroscience
- Epigenetics
- Developmental Biology
Background:
- Prenatal alcohol exposure causes fetal alcohol spectrum disorders (FASDs), leading to pediatric neurological defects and cognitive deficits.
- Mechanisms underlying alcohol-induced brain abnormalities, including hippocampal and neocortex dysfunction, are not fully understood.
Purpose of the Study:
- To investigate the persistent epigenetic mechanisms of neurodegeneration and cognitive decline in a postnatal ethanol exposure (PEE) animal model.
- To identify potential therapeutic targets for reversing alcohol-induced brain damage and cognitive deficits.
Main Methods:
- Utilized a postnatal ethanol exposure (PEE) animal model.
- Employed pharmacological, epigenetic, synaptic plasticity, and behavioral approaches.
- Investigated the role of histone deacetylases (HDACs) and cannabinoid receptor type-1 (CB1R) in PEE-induced neurodegeneration and cognitive deficits.
Main Results:
- PEE increased neurodegeneration markers (caspase-3) and histone deacetylase (HDAC1-HDAC3) levels while decreasing histone acetylation in neonatal brain regions.
- PEE repressed synaptic plasticity genes (e.g., Egr1, Arc) and led to HDAC enrichment at their promoter regions.
- Inhibition of HDACs with trichostatin A (TSA) or antagonism of CB1R before PEE reversed epigenetic changes, prevented neurodegeneration, and rescued cognitive deficits in adult mice.
Conclusions:
- CB1R/HDAC-mediated epigenetic remodeling disrupts gene expression, contributing to FASD-associated cognitive decline.
- Restoration of histone acetylation in the brain can reverse alcohol-induced epigenetic changes and ameliorate neurobehavioral defects.
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.
