Neuropharmacology

Biography

Biography: Alessandro Ieraci

Abstract

Physical exercise (PE) is an affordable and effective method to improve cognitive functions, mood and to prevent the stress-induced brain dysfunctions, partly by involving the action of brain-derived neurotrophic factor (BDNF). Although epigenetic modifications play a pivotal role in the regulation of the different BDNF transcripts, it is poorly understood whether both PE and stressful experiences modulate BDNF expression by epigenetic mechanisms. Moreover, a substantial variability of individual responses to PE and stressful experiences has been described. The reason for this is not known, but could be accounted for, among others, by individual genetic variants. We have found that PE and restraint stress (RS) have a complementary effect in controlling the total BDNF mRNA levels and specific BDNF transcripts expression in the hippocampus. Moreover, PE and RS differentially modulate the levels of histone H3 acetylation at the BDNF promoters and the histone deacetylases mRNA levels in the hippocampus. Interestingly, pretreatment with histone deacetylases inhibitors has similar efficacy as PE in preventing stress-induced down-regulation of BDNF transcripts. Remarkably, we have also found that PE-induced up-regulation of BDNF protein and BDNF transcripts are impaired in the knock-in mouse carrying the human BDNF Val66Met polymorphism. These deficiencies are accompanied by reduced PE-induced anxiolytic- and antidepressant-like response in BDNF Val66Met mutant mice. Overall, these results suggest that PE and RS are able to modulate complementary the expression of BDNF transcripts by different epigenetics mechanisms; and that the human BDNF Val66Met polymorphism impairs the PE-induced beneficial effects in mice.