title: Direct, complex effects of estrogens on basal forebrain cholinergic neurons.
abstract: Although controversial, estrogens remain one of the few agents purported to influence the incidence of Alzheimer's disease and one of their postulated mechanisms of action is their effects on basal forebrain cholinergic neurons. However, it is unclear whether the responses of cholinergic neurons to estrogens are direct or mediated via the retrograde influences of neurotrophins, known to be induced by estrogens in the hippocampus and neocortex. In the present study, we explore the issue of the primary site of action of estrogens by studying the regulation of expression of genes that characterize mature cholinergic neurons, i.e., choline acetyltransferase, trkA, and p75(NTR) in the medial septum and the nucleus basalis complex. In parallel, we study the hippocampal expression of NGF, BDNF, and NT-3, i.e., neurotrophins with known trophic roles on cholinergic neurons. Gene expression is studied by RT-PCR in ovariectomized female rats with and without estrogen supplementation within the physiological estradiol range and in rats with complete fimbria-fornix transactions treated with estrogen or vehicle. To clarify mechanisms of estrogen transduction in cholinergic neurons, we study the effects of estrogen treatment on fimbria-fornix-lesioned mice with genetic ablations of ER subtypes alpha and beta. The results of the present study suggest that, while estrogens do regulate BDNF expression in the hippocampus and neocortex, they also exert stimulatory non-trophic effects on basal forebrain cholinergic neurons, primarily on ChAT expression. Cholinergic neurons retain their ability to respond to estrogens after their complete separation from the hippocampus. The elimination of ERalpha alters significantly the phenotypic responsiveness of cholinergic neurons to estrogens, whereas elimination of ERbeta appears to have no effect. Our findings support the idea that estrogens directly enhance cholinergic neuron function and that ERalpha plays a significant role in transducing these regulatory effects.
authors.affiliation: Department of Pathology, Division of Neuropathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Bora
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Liu
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Kecojevic
authors.forename: Istvan
authors.initials: I
authors.lastname: Merchenthaler
authors.forename: Vassilis E
authors.initials: VE
authors.lastname: Koliatsos
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D019771:Axotomy; D020532:Basal Nucleus of Meynert / Q000187:drug effects* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002795:Choline O-Acetyltransferase / Q000235:genetics; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D020712:Fornix, Brain / Q000293:injuries / Q000601:surgery; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000235:genetics; D009414:Nerve Growth Factors / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020933:Neurotrophin 3 / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000235:genetics; D020665:Septum of Brain / Q000187:drug effects* / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D020917:Receptor, trkA