It has been shown that exogenous tPA administration increases hippocampal BDNF levels61 and the conversion of pro‐BDNF to BDNF by plasmin is essential for LTP late‐phases.62, 63 In addition, a defective tPA/plasmin/PAI‐1‐mediated BDNF maturation has been claimed to be involved in the manifestation of some brain pathologies, such as substance abuse and addiction,64, 65 depression,66 and stress.67 This evidence concerns the gene PLG and depressive disorder.