TY - JOUR
T1 - Direct, complex effects of estrogens on basal forebrain cholinergic neurons
AU - Bora, Susan H.
AU - Liu, Zhiping
AU - Kecojevic, Aleksandar
AU - Merchenthaler, Istvan
AU - Koliatsos, Vassilis E.
N1 - Funding Information:
We thank Ms. Annie Welch for her expert technical assistance. This work was supported by NIH grant RO1 AG16263.
PY - 2005/8
Y1 - 2005/8
N2 - 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 p75NTR 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 α and β. 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 ERα alters significantly the phenotypic responsiveness of cholinergic neurons to estrogens, whereas elimination of ERβ appears to have no effect. Our findings support the idea that estrogens directly enhance cholinergic neuron function and that ERα plays a significant role in transducing these regulatory effects.
AB - 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 p75NTR 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 α and β. 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 ERα alters significantly the phenotypic responsiveness of cholinergic neurons to estrogens, whereas elimination of ERβ appears to have no effect. Our findings support the idea that estrogens directly enhance cholinergic neuron function and that ERα plays a significant role in transducing these regulatory effects.
KW - Alzheimer's disease
KW - Brain
KW - Choline acetyltransferase
KW - Estrogen receptor
KW - Hippocampus
KW - Medial septum
KW - Menopause
KW - Neocortex
KW - Neurotrophins
KW - Nucleus basalis
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U2 - 10.1016/j.expneurol.2005.03.015
DO - 10.1016/j.expneurol.2005.03.015
M3 - Article
C2 - 15893308
AN - SCOPUS:22044455415
SN - 0014-4886
VL - 194
SP - 506
EP - 522
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -