Reduced function of the serotonin transporter is associated with decreased expression of BDNF in rodents as well as in humans.

In order to identify the molecular mechanisms that may contribute to the enhanced susceptibility to depression under serotonin transporter (SERT) dysfunction, we analyzed the expression of brain-derived neurotrophic factor (BDNF), a key player in neuronal plasticity, which is implicated in the etiology and treatment of depression. We found that BDNF levels were significantly reduced in the hippocampus and prefrontal cortex of SERT knockout rats, through transcriptional changes that affect different neurotrophin isoforms. The reduction of BDNF gene expression observed in prefrontal cortex is due, at least in part, to epigenetic changes that affect the promoter regions of exons IV and VI. Moreover, BDNF gene expression is also significantly reduced in leukocytes from healthy subjects carrying the S allele of the 5-HTTLPR, suggesting that the changes observed in SERT mutant rats may also be present in humans and may confer enhanced vulnerability to mood disorders.