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

2020 ◽  
Vol 23 (5) ◽  
pp. 324-338 ◽  
Author(s):  
Madhu Shivakumar ◽  
Shivakumar Subbanna ◽  
Vikram Joshi ◽  
Balapal S Basavarajappa
Keyword(s):  
Gene Expression ◽  
Synaptic Plasticity ◽  
Cognitive Decline ◽  
Ethanol Exposure ◽  
Epigenetic Mechanism ◽  
Fetal Alcohol ◽  
Adult Mice ◽  
Epigenetic Remodeling ◽  
Factor C ◽  
Fetal Alcohol Spectrum

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.

Neurobiology of Fetal Alcohol Spectrum Disorders

2017 ◽  
Author(s):  
Carmen Lopez-Arvizu ◽  
Carmel Bogle ◽  
Harolyn M.E. Belcher
Keyword(s):  
Hormonal Regulation ◽  
Maternal Nutrition ◽  
Fetal Alcohol Spectrum Disorders ◽  
Ethanol Exposure ◽  
Prenatal Ethanol Exposure ◽  
Fetal Alcohol ◽  
Wide Range ◽  
Spectrum Disorders ◽  
The Impact ◽  
Fetal Alcohol Spectrum

Prenatal exposure to ethanol can result in a wide range of clinical presentations that are grouped under the term “Fetal Alcohol Spectrum Disorders” (FASD). The direct cellular teratogenic effects of ethanol on fetal neurodevelopment include damage to cell survival, proliferation, and migration mechanisms. Dysregulation of neurotransmission and alteration of genetic transcription have also been implicated in the neurotoxic effects of prenatal ethanol exposure. These deleterious events lead to brain volume reduction, corpus callosum dysgenesis, cerebellar, and other neuroanatomical anomalies that have been observed in individuals with FASD. Beyond direct ethanol-induced insults, the impact that ethanol has on maternal nutrition, metabolism, hormonal regulation, and placental physiology also adversely effects fetal development. The complex interactions between numerous neurobiological and psychosocial mechanisms that hinder optimal fetal neurodevelopment are reflected by the heterogeneous clinical presentation of FASD, including impaired growth, dysmorphic facial features, and cognitive and behavioral disorders.

PCDHB14- and GABRB1-like nervous system developmental genes are altered during early neuronal differentiation of NCCIT cells treated with ethanol

2015 ◽  
Vol 34 (10) ◽  
pp. 1017-1027 ◽  
Author(s):  
D Halder ◽  
C Mandal ◽  
BH Lee ◽  
JS Lee ◽  
MR Choi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Neuronal Differentiation ◽  
Pathway Analysis ◽  
Synapse Formation ◽  
Fetal Alcohol Spectrum Disorders ◽  
Fetal Alcohol ◽  
Neuronal Precursors ◽  
The Central Nervous System ◽  
Fetal Alcohol Spectrum

Ethanol (EtOH) exposure during embryonic development causes dysfunction of the central nervous system (CNS). Here, we examined the effects of chronic EtOH on gene expression during early stages of neuronal differentiation. Human embryonic carcinoma (NCCIT) cells were differentiated into neuronal precursors/lineages in the presence or absence of EtOH and folic acid. Gene expression profiling and pathway analysis demonstrated that EtOH deregulates many genes and pathways that are involved in early brain development. EtOH exposure downregulated several important genes, such as PCDHB14, GABRB1, CTNND2, NAV3, RALDH1, and OPN5, which are involved in CNS development, synapse assembly, synaptic transmission, and neurotransmitter receptor activity. GeneGo pathway analysis revealed that the deregulated genes mapped to disease pathways that were relevant to fetal alcohol spectrum disorders (FASD, such as neurotic disorders, epilepsy, and alcohol-related disorders). In conclusion, these findings suggest that the impairment of the neurological system or suboptimal synapse formation resulting from EtOH exposure could underlie the neurodevelopmental disorders in individuals with FASD.

scholarly journals Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin

2021 ◽  
Vol 22 (13) ◽  
pp. 7083
Author(s):  
Malgorzata Lopatynska-Mazurek ◽  
Lukasz Komsta ◽  
Ewa Gibula-Tarlowska ◽  
Jolanta H. Kotlinska
Keyword(s):  
Oxidative Stress ◽  
Prefrontal Cortex ◽  
Learning And Memory ◽  
Fetal Alcohol Spectrum Disorders ◽  
Ethanol Exposure ◽  
Prenatal Ethanol Exposure ◽  
Aversive Learning ◽  
Fetal Alcohol ◽  
Spectrum Disorders ◽  
Fetal Alcohol Spectrum

Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin—a selective inhibitor of mTORC1, Torin-2—a non-selective mTORC1/mTORC2 inhibitor, and FK-506—a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4–9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.

scholarly journals Ethanol Exposure Alters Protein Expression in a Mouse Model of Fetal Alcohol Spectrum Disorders

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Stephen Mason ◽  
Bruce Anthony ◽  
Xianyin Lai ◽  
Heather N. Ringham ◽  
Mu Wang ◽  
...  
Keyword(s):  
Embryo Culture ◽  
Triosephosphate Isomerase ◽  
Fetal Alcohol Spectrum Disorders ◽  
Alcohol Exposure ◽  
Nervous System Development ◽  
Ethanol Exposure ◽  
Fetal Alcohol ◽  
Whole Embryo Culture ◽  
Spectrum Disorders ◽  
Fetal Alcohol Spectrum

Alcohol exposure during development can result in variable growth retardation and facial dysmorphology known as fetal alcohol spectrum disorders. Although the mechanisms underlying the disorder are not fully understood, recent progress has been made that alcohol induces aberrant changes in gene expression and in the epigenome of embryos. To inform the gene and epigenetic changes in alcohol-induced teratology, we used whole-embryo culture to identify the alcohol-signature protein profile of neurulating C6 mice. Alcohol-treated and control cultures were homogenized, isoelectrically focused, and loaded for 2D gel electrophoresis. Stained gels were cross matched with analytical software. We identified 40 differentially expressed protein spots (P<0.01), and 9 spots were selected for LC/MS-MS identification. Misregulated proteins include serotransferrin, triosephosphate isomerase and ubiquitin-conjugating enzyme E2 N. Misregulation of serotransferrin and triosephosphate isomerase was confirmed with immunologic analysis. Alteration of proteins with roles in cellular function, cell cycle, and the ubiquitin-proteasome pathway was induced by alcohol. Several misregulated proteins interact with effectors of the NF-κB and Myc transcription factor cascades. Using a whole-embryo culture, we have identified misregulated proteins known to be involved in nervous system development and function.

Sign in / Sign up

Export Citation Format

Share Document