LEVELS OF TRKA AND BDNF MESSENGER-RNA, BUT NOT NGF MESSENGER-RNA, FLUCTUATE ACROSS THE ESTROUS-CYCLE AND INCREASE IN RESPONSE TO ACUTE HORMONE REPLACEMENT

Recent studies suggest that hormone replacement therapy can help to re duce the risk and severity of Alzheimer's-related dementia in postmeno pausal 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 specif ic neurotrophins and neurotrophin receptors. In the present study, qua ntitative in situ hybridization techniques were used to determine whet her the levels of trkA mRNA in the basal forebrain, and nerve growth f actor (NGF) mRNA and brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus, are significantly affected by physiological changes i n circulating gonadal steroids. Gonadally intact animals were sacrific ed at different stages of the estrous cycle and ovariectomized animals were sacrificed at different times following the administration of ei ther estrogen or estrogen plus progesterone. In gonadally intact anima ls, 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 hor mone replacement, a significant increase (30.4%) in trkA mRNA was dete cted in the MS of animals sacrificed 24 h following estrogen administr ation. Levels of trkA mRNA in the MS declined to control levels over t he 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 mR NA 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 re ceiving estrogen and 5 h after receiving progesterone. No significant changes in trkA mRNA were detected in the nucleus basalis magnocellula ris, and no significant changes in NGF mRNA were detected in the hippo campus. These data demonstrate that levels of trkA mRNA in the MS, and BDNF mRNA in the hippocampus, are affected by physiological changes i n the levels of circulating gonadal steroids and are elevated in respo nse to acute hormone replacement. The relevance of these effects to th e ability for estrogen replacement to enhance cholinergic activity and hippocampal function, and thereby reduce the risk and severity of Alz heimer's-related dementia in postmenopausal women, is discussed. (C) 1 998 Elsevier Science B.V.