Inhibition of hippocampal estrogen synthesis causes region-specific downregulation of synaptic protein expression in hippocampal neurons

Abstract

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.

Aromatase Inhibition Abolishes LTP Generation in Female But Not in Male Mice

“…After 4 DIV, the incubation media were supplemented with letrozole (10 Ϫ7 M; kindly provided by Novartis) and letrozole plus 17 ␤-estradiol (10 Ϫ7 M, water soluble, Sigma-Aldrich) for 7 d. To test time-dependency, the effect of letrozole was additionally tested for various time intervals. Letrozole did not affect the viability of the cultures, as tested in previous experiments Prange-Kiel et al, 2006).…”

Morphine Protects against Intracellular Amyloid Toxicity by Inducing Estradiol Release and Upregulation of Hsp70

“…We also provide a novel mechanism for morphine action: induction of estradiol release by neurons, which is protective against iA␤ toxicity in our case. Although estrogen secretion by hippocampal neurons is described previously (Kretz et al, 2004;Prange-Kiel et al, 2006, 2008, this is the first time, to our knowledge, that induction of estradiol release in hippocampal neurons by morphine is reported. The efficacy of estrogen replacement therapy has been debated for a long time, and cognitive function is not necessarily improved after the therapy (Birge, 1996;Schneider and Finch, 1997;Mulnard, 2000;LeBlanc, 2002).…”

Insights into Rapid Modulation of Neuroplasticity by Brain Estrogens

“…Interestingly, a number of studies have also demonstrated that aromatase is located in postsynaptic structures (Naftolin et al, 1996;Kretz et al, 2004;Prange-Kiel et al, 2006). These data suggest that estrogens may be produced on either side of the synapse.…”