Brain‐derived neurotrophic factor expression is increased in the hippocampus of 5‐HT_2C receptor knockout mice

Abstract

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-HT(2C) receptor. Therefore, in this study we investigated BDNF expression in 5-HT(2C) receptor knockout mice (5-HT(2C) KO). 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-HT(2C) KO mice when compared with wild-type 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-HT(2C) KO (P = 0.003). BDNF mRNA expression in the hippocampus was not different between the genotypes. Hence, increased mature BDNF levels in 5-HT(2C) KO 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-HT(2C) KO 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-HT(2C) KO showed modest locomotor hyperactivity but no differences in tests for anxiety, sensorimotor gating, or depressive-like behaviors; however, in the tail suspension test 5-HT(2C) KO showed significantly reduced climbing (P < 0.05). In conclusion, loss of 5-HT(2C) 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-HT(2C) KO show only subtle behavioral changes.

Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation

“…A recent report by Hill and collaborators provides strong support to this hypothesis and suggests that serotonin would modulate BDNF levels via the activation of the 5-HT2C receptor. 55 In conclusion, our results demonstrate that serotonin, besides its role as a neurotransmitter, represents an important signal required during CNS development involved in the formation of the highly precise architecture of the nervous system and in particular in the fine tuning for patterning the correct serotonergic branching at selected regions of the brain. We also found that depletion of serotonin resulted in an up-regulation of BDNF expression in the hippocampus, thus matching the observed hyperinnervation.…”

Perturbation of Serotonin Homeostasis during Adulthood Affects Serotonergic Neuronal Circuitry

“…To investigate whether the increased density of serotonergic fibers in the hippocampus could be linked to an increase in the hippocampal brain-derived neurotrophic factor (BDNF) regulation that is known to be influenced by serotonin signaling (Hill et al, 2011; Migliarini et al, 2013; Homberg et al, 2014; Kronenberg et al, 2016), we analyzed BDNF mRNA expression levels performing ISH using 35 S-radiolabeled antisense BDNF probe on brain coronal sections of both TM- and vehicle-treated Tph2 GFP/fl ° x ::CMVCreER T mice at D30. Densitometric analysis of autoradiographic signal revealed that serotonin depletion did not impact BDNF mRNA transcriptional regulation (Fig.…”

“…As BDNF expression has been reported to be influenced by serotonin signaling (Hill et al, 2011; Migliarini et al, 2013; Homberg et al, 2014; Kronenberg et al, 2016), we wondered whether this neurotrophin could act as a potential molecular mediator in the establishment of the observed alterations in 5-HT fiber density. However, we failed to detect any significant alteration in the hippocampal level of BDNF in our Tph2 cKO mice, suggesting that other factors are likely involved in the response of 5-HT depletion during adult stages of life.…”

Neurotransmitters and Memory

“…Likewise, selective 5-HT 1B receptor antagonists facilitated memory in the water maze (Skelton et al, 2008), as well as did 5-HT-moduline a peptide endogenous (Moret et al, 2003) in autoshaped memory . In parallel to the finding that 5-HT 2B/2C receptors antagonist had no effect on autoshaped memory (Meneses, 2003), 5-HT 2C receptor knockout mice showed normal hidden platform and preference for the target quadrant during a probe trial (for references see Meneses, 2003) or with repeated training in a 10-day win-shift radial arm maze task, 5-HT 2C knock-out and wild type (WT) mice showed similar decreases of the number of working memory and reference memory errors (Hill et al, 2011).…”