Cholesterol-promoted synaptogenesis requires the conversion of cholesterol to estradiol in the hippocampus.
Cholesterol of glial origin promotes synaptogenesis (Mauch et al., (2001) Science 294:1354-1357). Because in the hippocampus local estradiol synthesis is essential for synaptogenesis, we addressed the question of whether cholesterol-promoted synapse formation results from the function of cholesterol as a precursor of estradiol synthesis in this brain area. To this end, we treated hippocampal cultures with cholesterol, estradiol, or with letrozole, a potent aromatase inhibitor. Cholesterol increased neuronal estradiol release into the medium, the number of spine synapses in hippocampal slice cultures, and immunoreactivity of synaptic proteins in dispersed cultures. Simultaneous application of cholesterol and letrozole or blockade of estrogen receptors by ICI 182 780 abolished cholesterol-induced synapse formation. As a further approach, we inhibited the access of cholesterol to the first enzyme of steroidogenesis by knock-down of steroidogenic acute regulatory protein, the rate-limiting step in steroidogenesis. A rescue of reduced synaptic protein expression in transfected cells was achieved by estradiol but not by cholesterol. Our data indicate that in the hippocampus cholesterol-promoted synapse formation requires the conversion of cholesterol to estradiol.
Fester
Lars
L
Institute of Anatomy I: Cellular Neurobiology, Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
Zhou
Lepu
L
Bütow
Andrea
A
Huber
Cornelia
C
von Lossow
Richard
R
Prange-Kiel
Janine
J
Jarry
Hubertus
H
Rune
Gabriele M
GM
D000818:Animals; D000831:Animals, Newborn; D047072:Aromatase Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D066298:In Vitro Techniques; D000077289:Letrozole; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009570:Nitriles / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D016708:Synaptophysin / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D000098682:Steroidogenic Acute Regulatory Protein; D000099273:Neurabins
D047072:Aromatase Inhibitors; D002784:Cholesterol; D004958:Estradiol; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D000077267:Fulvestrant; D000077289:Letrozole; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009570:Nitriles; D010750:Phosphoproteins; D016708:Synaptophysin; D014230:Triazoles; D000098682:Steroidogenic Acute Regulatory Protein; D000099273:Neurabins