Electroconvulsive therapy is the most effective treatment for antidepressant-resistant depression, although its mechanism has not been fully elucidated. Previous studies have demonstrated that electroconvulsive seizures (ECS) induce expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus. However, in contrast with mature BDNF (mBDNF) known to have antidepressant effects, its precursor (pro-BDNF) has harmful effects on neurons. We therefore hypothesized that efficient

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... sing of pro-BDNF is a critical requirement for the antidepressant effects of ECS. We found that single administration of ECS rapidly increased not only hippocampal levels of pro-BDNF but also those of prohormone convertase 1 (PC1) and tissue-plasminogen activator (t-PA), which are proteases involved in intra-and extracellular pro-BDNF processing, respectively. Interestingly, pro-BDNF and t-PA levels were increased in hippocampal synaptosomes after single ECS, suggesting their transport to secretory sites. In rats receiving 10-d repeated ECS, accumulation of pro-BDNF and a resultant increase in mBDNF levels were observed. While t-PA levels increased and accumulated following repeated ECS, PC1 levels did not, suggesting that intracellular processing capacity is limited. Finally, chronic administration of imipramine significantly increased mBDNF levels, but not pro-BDNF and protease levels, indicating that the therapeutic mechanism of imipramine differs from that of ECS. Taken together, these results suggest that, while intra-and extracellular proteases are involved in pro-BDNF processing in single ECS, t-PA plays a dominant role following repeated ECS. Such efficient pro-BDNF processing as well as strong induction of BDNF expression may contribute to the antidepressant effects of ECS.