Estradiol responsiveness of synaptopodin in hippocampal neurons is mediated by estrogen receptor β.
In the hippocampus, synaptic proteins, as studied so far, have been shown to be upregulated by 17β-estradiol, while inhibition of local estradiol synthesis consistently downregulates them. As an exception to this rule, we have previously shown that synaptopodin, an actin-associated postsynaptic protein, is downregulated in response to estradiol in dissociated cultured hippocampal neurons. In this study, we show, unexpectedly, that synaptopodin is downregulated in the hippocampus of aromatase knock-out mice and that inhibition of neuronal estradiol synthesis using the aromatase inhibitor letrozole also downregulates synaptopodin in these cultures. Moreover, the effects of estradiol and letrozole are additive, suggesting a subtle balance between available ligand and receptor. Using selective estrogen receptor agonists and antagonists, we consequently studied the effects of estrogen receptor subtypes on synaptopodin expression in our hippocampal cultures. We found that estradiol-induced downregulation of synaptopodin is mediated by estrogen receptor β. Estrogen receptor β in turn, is upregulated in response to intracellular estradiol ablation following inhibition of estradiol synthesis by letrozole in dissociated hippocampal cultures, as well as in the hippocampus of the aromatase knock-out mouse. Thus, it appears that both the application of estradiol, via binding to estrogen receptor β, and letrozole, via upregulation of estrogen receptor β, eventually result in a downregulation of synaptopodin. Our data show that the synaptic plasticity caused by estradiol is subject to a subtle balance of the levels of estrogen receptor subtypes regulated by the available ligands. In addition, both seem to be part of a homeostatic feedback mechanism.
Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
Lars
L
Fester
Jan
J
Labitzke
Rebecca
R
Hinz
Christoph
C
Behem
Katja
K
Horling
Theresa
T
Bernhard
Manuela I
MI
Bader
Günter
G
Vollmer
Gabriele M
GM
Rune
D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology*; D007150:Immunohistochemistry; D000077289:Letrozole; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D014230:Triazoles / Q000494:pharmacology
D047629:Estrogen Receptor beta; D008840:Microfilament Proteins; D009570:Nitriles; C503968:Synpo protein, mouse; C503969:Synpo protein, rat; D014230:Triazoles; D004958:Estradiol; D000077289:Letrozole; D001141:Aromatase
Aromatase; Estrogen; Estrogen receptor; Synaptic proteins; Synaptopodin