Research ReportSex-specific and region-specific changes in BDNF-TrkB signalling in the hippocampus of 5-HT1A receptor and BDNF single and double mutant mice

Brain-derived neurotrophic factor (BDNF) and serotonin 5-HT1A receptors are implicated in the pathophysiology of depression and the mechanism of action of antidepressant drugs. Here, we explore possible reciprocal interactions of 5-HT1A receptor knockout and the expression of BDNF, its receptor TrkB and downstream mitogen-activated protein kinase (MAPK) in the ventral (VHP) and dorsal hippocampus (DHP). We compared female and male double mutant mice (5-HT1A−/−/BDNF+/−) with single mutant mice (5-HT1A−/−, BDNF+/−) and wildtype (WT) controls. Protein expression of BDNF, TrkB, phosphorylation of TrkB (pTrkB) and MAPKs (ERK1, ERK2) was examined using Western blot analysis (n = 5-7). As expected, the BDNF+/− mice showed ~ 50% BDNF reduction. Loss of 5-HT1A receptors induced a significant decrease in BDNF levels in the VHP in female mice. The pTrkB/TrkB ratio was also significantly decreased in female 5-HT1A−/− mice and 5-HT1A−/−/BDNF+/− mice but not in males. Despite markedly reduced BDNF levels in BDNF+/− mice and double mutants, ERK1 activation was unchanged in the female mice. In contrast, ERK2 activation was significantly elevated in the VHP of female BDNF+/− mice and double mutants. Given the greater vulnerability of women to develop depression and the role of the VHP in stress responses and anxiety-related behaviours, our results may shed more light on sex differences in depression and other psychiatric disorders with BDNF and 5-HT1A receptor dysfunction.

► 5-HT1A−/− genotype decreases BDNF protein expression. ► 5-HT1A−/− and BDNF+/−/5-HT1A−/− decreases TrkB phosphorylation. ► BDNF+/− and BDNF+/−/5-HT1A−/− elevates ERK2 phosphorylation compared to 5-HT1A−/−. ► These results are specific to the ventral hippocampus of female mice and not male mice.