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A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood

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Abstract

Binge drinking during adolescence is a risk factor for neuropsychiatric disorders that can develop later in life. Histone acetylation is an important epigenetic mechanism that contributes to neurodevelopment. We investigated the effects of adolescent intermittent ethanol (AIE) exposure, as opposed to normal saline (AIS) exposure, on histone acetylation-mediated regulation of brain-derived neurotrophic factor (BDNF) expression and developmental stages of neurogenesis (proliferating and immature neurons) in the hippocampus in adulthood. AIE exposure increased whole hippocampal histone deacetylase (HDAC) activity and decreased binding protein of cyclic adenosine monophosphate response element binding protein (CBP) and histone H3-K9 acetylation levels in the CA1, CA2, and CA3 regions of the hippocampus. BDNF protein and exon IV mRNA levels in the CA1 and CA3 regions of the hippocampus of AIE-exposed adult rats were decreased as compared to AIS-exposed adult rats. AIE-induced anxiety-like behaviors and deficits in histone H3 acetylation at BDNF exon IV promoter in the hippocampus during adulthood, which were reversed by treatment with the HDAC inhibitor, trichostatin A (TSA). Similarly, neurogenesis was inhibited by AIE in adulthood as demonstrated by the decrease in Ki-67 and doublecortin (DCX)-positive cells in the dentate gyrus, which was normalized by TSA treatment. These results indicate that AIE exposure increases HDACs and decreases CBP levels that may be associated with a decrease in histone H3 acetylation in the hippocampus. These epigenetic changes potentially decrease BDNF expression and inhibit neurogenesis in the hippocampus that may be involved in AIE-induced behavioral abnormalities, including anxiety, in adulthood.

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Acknowledgments

This work was supported by the grants from National Institute on Alcohol Abuse and Alcoholism [Neurobiology of Adolescent Drinking in Adulthood (NADIA, AA-019971 and U24AA-024605), AA-010005, AA-013341, and P50 AA-022538], and by the Department of Veterans Affairs (Merit Review Grant, I01BX000143; Senior Research Career Scientist award) to SCP and AA020023 (NADIA project), AA020024, and AA020022 to FTC. DMK was supported by Raman post-doctoral research fellowship from the University Grant Commission, New Delhi, India.

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Authors and Affiliations

  1. Department of Psychiatry, Center for Alcohol Research in Epigenetics (CARE), University of Illinois at Chicago, 1601 West Taylor Street (m/c 912), Chicago, IL, 60612, USA

    Amul J. Sakharkar, Huaibo Zhang, Dadasaheb M. Kokare & Subhash C. Pandey

  2. Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Subhash C. Pandey

  3. Jesse Brown Veterans Affairs Medical Center, Chicago, IL, 60612, USA

    Amul J. Sakharkar, Huaibo Zhang & Subhash C. Pandey

  4. Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Ryan P. Vetreno & Fulton T. Crews

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  1. Amul J. Sakharkar
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Correspondence to Subhash C. Pandey.

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No biomedical financial interests or potential conflicts of interest were reported by other authors. SCP reports that a US patent application entitled “Histone acetyl transferase activators and histone deacetylase inhibitors in the treatment of alcoholism” (serial number 60/848237 filed on September 29th, 2006) is currently pending.

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Sakharkar, A.J., Vetreno, R.P., Zhang, H. et al. A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood. Brain Struct Funct 221, 4691–4703 (2016). https://doi.org/10.1007/s00429-016-1196-y

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