Sarah Momin

 Introduction. Fetal Alcohol Syndrome (FAS) is the most severe disability outcome in the spectrum of conditions related to alcohol teratogenicity and presents with craniofacial dysmorphology and a broad range of neurodevelopmental and anatomical anomalies. These include speech and hearing deficits, muscular and cranial nerve dysfunction, vascular changes, and neurobehavioral and intellectual disabilities, such as ADHD and deficits in executive function. According to the CDC, there is an estimated 1-5% of children who suffer from FASDs in the US and some western European countries¹. There are currently no FDA approved drugs to treat FAS. Several studies have highlighted that histone deacetylases (HDACs) are upregulated, serving as a common pathway for epigenetic modifications that may result in adverse cellular outcomes like increased apoptosis, as well as neurobehavioral outcomes including deficits in learning and memory, and increased anxiety.^2-5 Other studies have linked HDAC activity to alcohol dependence.⁶ Various studies described HDAC inhibition as improving outcomes in FAS animal models.^2-5 These findings could improve understanding of potential downstream pathways to target as treatments for FAS. Methods. Montagud-Romero et al used alcohol-exposed C57BL/6 female pregnant mice to model binge drinking during gestation and lactation. Male offspring were treated postnatally on days 28-35 with a class I and II HDAC inhibitor, Trichostatin A (TSA) and behaviorally analyzed on days 36-55. Underlying mechanisms affecting behavior were observed by evaluating expression of brain-derived neurotrophic factor (BDNF) in distinct brain regions and newly differentiated neurons in the dentate gyrus (DG).⁵  Results. Alcohol-exposed mice offspring tested in an elevated plus maze, presented with anxiogenic-like responses that slightly improved after TSA administration. In a Y-maze assay, used to evaluate spatial working memory, alcohol-exposed mice exhibited significant impairment that were improved greatly with TSA. Alcohol-exposed offspring also showed lower recognition index scores on a novel object recognition assay used to study learning and memory, with slight improvement resulting from TSA treatment. Alcohol-exposed mice exhibited decreased BDNF levels in the hippocampus compared to the control group, and mice treated with TSA showed a higher level of phospho-CREB relative to total CREB, an index of neuroprotection. TSA improved neurogenesis in the dentate gyrus of mice exposed to alcohol.⁵ Conclusion. HDAC activity is a common epigenetic precursor to many downstream pathways associated with FAS including apoptosis, learning and memory, anxiety behaviors, brain development, and alcohol dependence. TSA as an HDAC inhibitor requires further understanding of downstream effectors and their role in behavior, learning, and memory, so future therapies can be more target specific.

1. gov. (2021). Fetal Alcohol Spectrum Disorders (FASDs) Homepage. [online] Available at: https://www.cdc.gov/ncbddd/fasd/data.html [Accessed 14 May 2021].
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3. Drissi I, Deschamps C, Fouquet G, et al. Memory and plasticity impairment after binge drinking in adolescent rat hippocampus: GluN2A/GluN2B NMDA receptor subunits imbalance through HDAC2. Addict Biol. 2020;25(3):e12760. doi:10.1111/adb.12760
4. Topuz RD, Gunduz O, Tastekin E, Karadag CH. Effects of hippocampal histone acetylation and HDAC inhibition on spatial learning and memory in the Morris water maze in rats. Fundam Clin Pharmacol. 2020;34(2):222-228. doi:10.1111/fcp.12512
5. Montagud-Romero S, Cantacorps L, Valverde O. Histone deacetylases inhibitor trichostatin A reverses anxiety-like symptoms and memory impairments induced by maternal binge alcohol drinking in mice. J Psychopharmacol. 2019;33(12):1573-1587. doi:10.1177/0269881119857208
6. Bohnsack JP, Patel VK, Morrow AL. Ethanol Exposure Regulates Gabra1 Expression via Histone Deacetylation at the Promoter in Cultured Cortical Neurons. J Pharmacol Exp Ther. 2017;363(1):1-11. doi:10.1124/jpet.117.242446