title: Estrogen-regulated synaptogenesis in the hippocampus: sexual dimorphism in vivo but not in vitro.
abstract: Hippocampal neurons are capable of synthesizing estradiol de novo. Estradiol synthesis can be suppressed by aromatase inhibitors and by knock-down of steroid acute regulatory protein (StAR), whereas elevated levels of substrates of steroidogenesis enhance estradiol synthesis. In rat hippocampal cultures, the expression of estrogen receptors (ERs) and synaptic proteins, as well as synapse density, correlated positively with aromatase activity, regardless of whether the cultures originated from males or females. All effects induced by the inhibition of aromatase activity were rescued by application of estradiol to the cultures. In vivo, however, systemic application of letrozole, an aromatase inhibitor, induced synapse loss in female rats, but not in males. Furthermore, in the female hippocampus, density of spines and spine synapses varied with the estrus cycle. In addressing this in vivo-in vitro discrepancy, we found that gonadotropin-releasing hormone (GnRH) regulated estradiol synthesis via an aromatase-mediated mechanism and consistently regulated spine synapse density and the expression of synaptic proteins. Along these lines, GnRH receptor density was higher in the hippocampus than in the cortex and hypothalamus, and estrus cyclicity of spinogenesis was found in the hippocampus, but not in the cortex. Since GnRH receptor expression also varies with the estrus cycle, the sexual dimorphism in estrogen-regulated spine synapse density in the hippocampus very likely results from differences in the GnRH responsiveness of the male and the female hippocampus. This article is part of a Special Issue entitled 'Neurosteroids'.
authors.affiliation: Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Fester
authors.forename: Janine
authors.initials: J
authors.lastname: Prange-Kiel
authors.forename: Lepu
authors.initials: L
authors.lastname: Zhou
authors.forename: Breda V
authors.initials: BV
authors.lastname: Blittersdorf
authors.forename: Julia
authors.initials: J
authors.lastname: Böhm
authors.forename: Hubertus
authors.initials: H
authors.lastname: Jarry
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
authors.forename: Gabriele M
authors.initials: GM
authors.lastname: Rune
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000096:biosynthesis / Q000502:physiology*; D004971:Estrus / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism; D000077289:Letrozole; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D011960:Receptors, Estrogen / Q000096:biosynthesis; D012737:Sex Factors; D013569:Synapses / Q000187:drug effects* / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D004958:Estradiol; D000077289:Letrozole; D001141:Aromatase