Levels of trkA and BDNF mRNA, but not NGF mRNA, fluctuate across the estrous cycle and increase in response to acute hormone replacement

Abstract

Recent studies suggest that hormone replacement therapy can help to reduce the risk and severity of Alzheimer's-related dementia in postmenopausal women. We have hypothesized that these effects are due, in part, to the ability for estrogen and progesterone to enhance hippocampal function, as well as the functional status of cholinergic projections to the hippocampus and cortex, by influencing the expression of specific neurotrophins and neurotrophin receptors. In the present study, quantitative in situ hybridization techniques were used to determine whether the levels of trkA mRNA in the basal forebrain, and nerve growth factor (NGF) mRNA and brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus, are significantly affected by physiological changes in circulating gonadal steroids. Gonadally intact animals were sacrificed at different stages of the estrous cycle and ovariectomized animals were sacrificed at different times following the administration of either estrogen or estrogen plus progesterone. In gonadally intact animals, significant fluctuations in the levels of trkA mRNA in the medial septum (MS), and BDNF mRNA in regions CA1 and CA3/4 of the hippocampus, were detected across the estrous cycle. In animals that received hormone replacement, a significant increase (30.4%) in trkA mRNA was detected in the MS of animals sacrificed 24 h following estrogen administration. Levels of trkA mRNA in the MS declined to control levels over the next 48 h; however, a single injection of progesterone administered 48 h after estradiol appeared to prevent any further decline in trkA mRNA over the next 24 h. In addition, significant increases in BDNF mRNA were detected in the dentate granule cell layer (73.4%), region CA1 (28.1%), and region CA3/4 (76.9%) of animals sacrificed 53 h after receiving estrogen and 5 h after receiving progesterone. No significant changes in trkA mRNA were detected in the nucleus basalis magnocellularis, and no significant changes in NGF mRNA were detected in the hippocampus. These data demonstrate that levels of trkA mRNA in the MS, and BDNF mRNA in the hippocampus, are affected by physiological changes in the levels of circulating gonadal steroids and are elevated in response to acute hormone replacement. The relevance of these effects to the ability for estrogen replacement to enhance cholinergic activity and hippocampal function, and thereby reduce the risk and severity of Alzheimer's-related dementia in postmenopausal women, is discussed.