Inhibition of hippocampal estrogen synthesis causes region-specific downregulation of synaptic protein expression in hippocampal neurons.
Previous studies have shown that synapses and expression of synaptic proteins in hippocampal neurons are regulated by hippocampus-derived estradiol. Here, we compared the effects of this paracrine regulation in different hippocampal regions. In tissue sections, immunohistochemistry followed by semiquantitative image analysis revealed a three-fold higher expression of steroidogenic acute regulatory protein (StAR) and aromatase in neurons of the CA3 than that of the CA1 region and in granule cells. Next, we treated hippocampal cell cultures with letrozole, an aromatase inhibitor, which resulted in a dose-dependent decrease in the release of 17beta-estradiol into the medium and in a dose-dependent downregulation of spinophilin and synaptophysin expression in dissociated hippocampal neurons. The downregulation of synaptic protein expression was restored by simultaneous application of letrozole together with estradiol. In response to a defined dose of letrozole, the downregulation of spinophilin expression was significantly stronger in CA1 neurons and in granule cells, than in cells of the CA3 region in slice cultures. With synaptophysin, downregulation was stronger in stratum lucidum of CA3 than in stratum radiatum of CA1. Both region-specific expression of steroidogenic enzymes and region-specific downregulation of synaptic proteins in response to a defined dose of letrozole may suggest different levels of estrogen concentrations within the hippocampus. Varying concentrations of estradiol in the hippocampus in turn may contribute to region-specific differentiation of hippocampal neurons.
Prange-Kiel
Janine
J
Department of Anatomy I: Cellular Neurobiology, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
Fester
Lars
L
Zhou
Lepu
L
Lauke
Heidrun
H
Carrétero
Jose
J
Rune
Gabriele M
GM
D000818:Animals; D001141:Aromatase / Q000096:biosynthesis; D047072:Aromatase Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000096:biosynthesis*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D000077289:Letrozole; D008840:Microfilament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010750:Phosphoproteins / Q000096:biosynthesis; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D000098682:Steroidogenic Acute Regulatory Protein; D000099273:Neurabins
D001141:Aromatase; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004967:Estrogens; D000077289:Letrozole; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009570:Nitriles; D010750:Phosphoproteins; D016708:Synaptophysin; D014230:Triazoles; D000098682:Steroidogenic Acute Regulatory Protein; D000099273:Neurabins