title: Sex-specific and region-specific changes in BDNF-TrkB signalling in the hippocampus of 5-HT1A receptor and BDNF single and double mutant mice.
abstract: 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.
authors.affiliation: Behavioural Neuroscience Laboratory, Mental Health Research Institute, Parkville, Melbourne, Australia.
authors.forename: YeeWen Candace
authors.initials: YC
authors.lastname: Wu
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Hill
authors.forename: Maren
authors.initials: M
authors.lastname: Klug
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Buuse
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003863:Depression / Q000235:genetics / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009928:Organ Specificity; D010766:Phosphorylation; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D020917:Receptor, trkA / Q000378:metabolism*; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D044282:Receptor, Serotonin, 5-HT1A; D020917:Receptor, trkA; D020928:Mitogen-Activated Protein Kinases