TY - JOUR
T1 - Sex-specific and region-specific changes in BDNF-TrkB signalling in the hippocampus of 5-HT1A receptor and BDNF single and double mutant mice.
AU - Wu, Yee Wen Candace
AU - Hill, Rachel Anne
AU - Klug, Maren
AU - van den Buuse, Maarten
PY - 2012/5/3
Y1 - 2012/5/3
N2 - 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.
AB - 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.
U2 - 10.1016/j.brainres.2012.03.011
DO - 10.1016/j.brainres.2012.03.011
M3 - Article
VL - 1452
SP - 10
EP - 17
JO - Brain Research
JF - Brain Research
SN - 0006-8993
ER -