Hippocampal Synapses Depend on Hippocampal Estrogen Synthesis

Abstract

Estrogens have been described to induce synaptogenesis in principal neurons of the hippocampus and have been shown to be synthesized and released by exactly these neurons. Here, we have focused on the significance of local estrogen synthesis on spine synapse formation and the synthesis of synaptic proteins. To this end, we reduced hippocampal estrogen synthesis in vitro with letrozole, a reversible nonsteroidal aromatase inhibitor. In hippocampal slice cultures, letrozole treatment resulted in a dose-dependent decrease of 17␤-estradiol as quantified by RIA. This was accompanied by a significant decrease in the density of spine synapses and in the number of presynaptic boutons. Quantitative immunohistochemistry revealed a downregulation of spinophilin, a marker of dendritic spines, and synaptophysin, a protein of presynaptic vesicles, in response to letrozole. Surprisingly, no increase in the density of spines, boutons, and synapses and in spinophilin expression was seen after application of estradiol to the medium of cultures that had not been treated with letrozole. However, synaptophysin expression was upregulated under these conditions. Our results point to an essential role of endogenous hippocampal estrogen synthesis in the maintenance of hippocampal spine synapses.

Duration of estrogen deprivation, not chronological age, prevents estrogen's ability to enhance hippocampal synaptic physiology

“…Because BDNF expression is highest at proestrus (54), the decrease in endogenous E2 with aging will lead to decreased BDNF expression and contribute to the loss of E2's beneficial effects. Additional related factors include the impact of ovarian E2 depletion on local estrogen synthesis in hippocampus, which was recently shown to be critical for hippocampal function (54).…”

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

“…The effects of estradiol on spine density and LTP were frequently shown by either using ovariectomized animals, which had been treated systemically with estradiol (Gould et al, 1990;Warren et al, 1995;Có rdoba Montoya and Carrer, 1997;Smith and McMahon, 2005;Kramár et al, 2009), by applying estradiol to acute slices of mostly male rats (Foy et al, 1999;Ito et al, 1999;Mukai et al, 2007;Kramár et al, 2009), or by using mixed hippocampal slice cultures from neonatal males and females (Murphy and Segal, 1996;Kretz et al, 2004;Mendez et al, 2011). Thus, the vast majority of studies do not consider the potential differences between males and females.…”

“…We have already demonstrated that hippocampal neurons are capable of synthesizing estradiol de novo (Wehrenberg et al, 2001;Prange-Kiel et al, 2003) and that hippocampus-derived estradiol is required for the maintenance of hippocampal synapses (Kretz et al, 2004). Letrozole, which is a nonsteroidal aromatase inhibitor and is commonly used in the therapy of breast cancer, reliably inhibits estradiol synthesis.…”

Ovariectomy increases neuronal amyloid-β binding alcohol dehydrogenase level in the mouse hippocampus

“…Similarly, recent data also indicated that OVX for 3 months, by which serum estrogen level were markedly decreased, did not affect estrogen level and Aβ plaque formation in the brains of AD model transgenic mice (APP23) overexpressing a mutant amyloid precursor protein transgene, but significantly decreased the brain estrogen level followed by Aβ plaque formation in APP23 mice with an aromatase gene knockout (Yue et al, 2005). In addition, it has been reported that reducing estrogen levels by blocking aromatase activity with letrozole, a reversible non-steroidal aromatase inhibitor, reduces the density of spines and synapses in hippocampal slice cultures (Kretz et al, 2004). These findings suggest that brain-derived estrogens, which are converted from C19 steroids by aromatase, have more important role in the Aβ clearance and the maintenance of neural environment than ovary-derived estrogens.…”