Brain-Derived Neurotrophic Factor Expression Is Increased in the Hippocampus of 5-HT2C Receptor Knockout Mice

Several studies have suggested a close interaction between serotonin (5-HT) and BDNF; however, little is known of the specific relationship between BDNF and the 5-HT2C receptor. Therefore, in this study we investigated BDNF expression in 5-HT2C receptor knockout mice (5-HT2CKO). We also assessed functional consequences of any changes in BDNF using a behavioral test battery. Western blot analysis demonstrated a significant 2.2-fold increase in the expression of the mature form of BDNF in 5-HT2CKO mice when compared with wildtype controls (WT) in the hippocampus (P = 0.008), but not frontal cortex or striatum. No differences in the expression of the pro-BDNF isoform were found, and the ratio of mature/pro BDNF was significantly increased in 5-HT2CKO (P = 0.003). BDNF mRNA expression in the hippocampus was not different between the genotypes. Hence, increased mature BDNF levels in 5-HT2CKO hippocampus are most likely due to increased extracellular cleavage rates of pro-BDNF to its mature form. Protein expression of the BDNF receptor, tropomycin-related receptor B (TrkB), was also unchanged in the hippocampus, frontal cortex and striatum. With repeated training in a 10-day win-shift radial arm maze task, 5-HT2CKO and WT showed similar decreases of the number of working memory and reference memory errors. In addition, no genotype specific differences were observed for passive or active avoidance learning. 5-HT2CKO showed modest locomotor hyperactivity but no differences in tests for anxiety, sensorimotor gating, or depressive-like behaviors; however, in the tail suspension test 5-HT2CKO showed significantly reduced climbing (P < 0.05). In conclusion, loss of 5-HT2C receptor expression leads to a marked and selective increase in levels of the mature form of BDNF in the hippocampus. Despite this marked increase, 5-HT2CKO show only subtle behavioral changes. (C) 2010 Wiley-Liss, Inc.