Histone deacetylases inhibitor trichostatin A reverses anxiety-like symptoms and memory impairments induced by maternal binge alcohol drinking in mice

Background: Alcohol exposure during development has detrimental effects, including a wide range of physical, cognitive and neurobehavioural anomalies known as foetal alcohol spectrum disorders. However, alcohol consumption among pregnant woman is an ongoing latent health problem. Aim: In the present study, the effects of trichostatin A (TSA) on emotional and cognitive impairments caused by prenatal and lactational alcohol exposure were assessed. TSA is an inhibitor of class I and II histone deacetylases enzymes (HDAC), and for that, HDAC4 activity was determined. We also evaluated mechanisms underlying the behavioural effects observed, including the expression of brain-derived neurotrophic factor (BDNF) in discrete brain regions and newly differentiated neurons in the dentate gyrus (DG). Methods: C57BL/6 female pregnant mice were used, with limited access to a 20% v/v alcohol solution as a procedure to model binge alcohol drinking during gestation and lactation. Male offspring were treated with TSA during the postnatal days (PD28-35) and behaviourally evaluated (PD36-55). Results: Early alcohol exposure mice presented increased anxiogenic-like responses and memory deterioration - effects that were partially reversed with TSA. Early alcohol exposure produces a decrease in BDNF levels in the hippocampus (HPC) and prefrontal cortex, a reduction of neurogenesis in the DG and increased activity levels of the HDAC4 in the HPC. Conclusions: Such findings support the participation of HDAC enzymes in cognitive and emotional alterations induced by binge alcohol consumption during gestation and lactation and would indicate potential benefits of HDAC inhibitors for some aspects of foetal alcohol spectrum disorders. The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was supported by the Ministerio de Economía y Competitividad (Spanish Ministry of Economy and Competitiveness – grant number SAF2016-75966-R-FEDER), and the Spanish Ministry of Health (Retic-ISCIII-RD16/0017/0010 and PNSD 2018/007). SM-R received a postdoctoral fellowship from the Conselleria d’Educació, Investigació, Cultura i Esport (APOSTD/2017/102), Generalitat Valenciana, Spain. LC received an FPI grant (BES-2014-070657) from the Ministerio de Economía y Competitividad, The Department of Experimental and Health Sciences (UPF), ‘Unidad de Excelencia María de Maeztu’ funded by the MINECO (ref. MDM-2014-0370).