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Female hippocampal estrogens have a significant correlation with cyclic fluctuation of hippocampal spines.

ABSTRACT: Synaptic plasticity of the female hippocampus may cyclically fluctuate across the estrous cycle. The spine density fluctuation had been explained by fluctuation of plasma estradiol (E2) and progesterone (PROG), with the assumption that these steroids penetrate into the hippocampus. Recently, however, we demonstrated that male hippocampal levels of sex steroids are much higher than those in plasma, suggesting a weak contribution of plasma steroids to the spine density. By combination of mass-spectrometric analysis with HPLC-purification and picolinoyl-derivatization of hippocampal sex steroids, we determined the accurate concentration of E2 and PROG at four stages of plasma estrous cycle including Proestrus (Pro), Estrus (Est), Diestrus 1 (D1), and Diestrus 2 (D2). Hippocampal levels of E2 and PROG showed cyclic fluctuation with a peak at Pro for E2 and at D1 for PROG, having a positive correlation with the plasma estrous cycle. All these sex steroid levels are much higher in the hippocampus than in plasma. Even after ovariectomy a significant levels of E2 and PROG were observed in the hippocampus. The total spine density showed higher values at Pro and D1, and lower values at Est and D2, having a good correlation with the peak levels of hippocampal E2 or PROG. We also examined fluctuation of the head diameter of spines. Interestingly, mRNA expression level of steroidogenic enzymes (P450arom and 17β-HSD, etc.) and sex-steroid receptors did not significantly change across the estrous cycle. Therefore, the fluctuation of total hippocampal PROG (equal to sum of hippocampus-synthesized PROG and plasma PROG) may be originated from the contribution of cyclic change in plasma PROG, which can induce the fluctuation of total hippocampal E2, since steroid conversion activity of hippocampus might be nearly the same across the estrus cycle.

SUBMITTER: Kato A

PROVIDER: S-EPMC3798982 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Autocrine/paracrine factors generated in response to 17β-estradiol (E2) within the fallopian tube (FT) facilitate fertilization and early embryo development for implantation. Since cyclic AMP (cAMP) plays a key role in reproduction, regulation of its synthesis by E2 may be of biological/pathophysiological relevance. Herein, we investigated whether cAMP production in FT cells (FTCs) is regulated by E2 and environmental estrogens (EE's; xenoestrogens and phytoestrogens). Under basal conditions, low levels of extracellular cAMP were detectable in bovine FTCs (epithelial cells and fibroblasts; 1:1 ratio). Treatment of FTCs with forskolin (AC; adenylyl cyclase activator), isoproterenol (β-adrenoceptor agonist) and IBMX (phosphodiesterase (PDE) inhibitor) dramatically (>10 fold) increased cAMP; whereas LRE1 (sAC; soluble AC inhibitor) and 2',5'-dideoxyadenosine (DDA; transmembrane AC (tmAC)) inhibitor decreased cAMP. Comparable changes in basal and stimulated intracellular cAMP were also observed. Ro-20-1724 (PDE-IV inhibitor), but not milrinone (PDE-III inhibitor) nor mmIBMX (PDE-I inhibitor), augmented forskolin-stimulated cAMP levels, suggesting that PDE-IV dominates in FTCs. E2 increased cAMP levels and CREB phosphorylation in FTCs, and these effects were mimicked by EE's (genistein, 4-hydroxy-2',4',6'-trichlorobiphenyl, 4-hydroxy-2',4',6'-dichlorobiphenyl). Moreover, the effects of E2 and EE were blocked by the tmAC inhibitor DDA, but not by the ERα/β antagonist ICI182780. Moreover, BAPTA-AM (intracellular-Ca2+ chelator) abrogated the effects of E2, but not genistein, on cAMP suggesting differential involvement of Ca2+. Treatment with non-permeable E2-BSA induced cAMP levels and CREB-phosphorylation; moreover, the stimulatory effects of E2 and EEs on cAMP were blocked by G15, a G protein-coupled estrogen receptor (GPER) antagonist. E2 and IBMX induced cAMP formation was inhibited by LRE1 and DDA suggesting involvement of both tmAC and sAC. Our results provide the first evidence that in FTCs, E2 and EE's stimulate cAMP synthesis via GPER. Exposure of the FT to EE's and PDE inhibitors may result in abnormal non-cyclic induction of cAMP levels which may induce deleterious effects on reproduction.

Project description:Depression is a highly prevalent psychiatric disorder, impacting females at a rate roughly twice that of males. This disparity has become the focus of many studies which are working to determine if there are environmental or biological underpinnings to depression pathology. The biology of depression is not well understood, but experts agree that a key neurotransmitter of interest is serotonin. Most research on basic serotonin neurochemistry, by us and others, has predominantly focused on male models. Thus, it is now critical to include female models to decipher possible fundamental differences between the sexes that may underlie this disorder. In this paper, we seek to determine any such differences using fast-scan cyclic voltammetry (FSCV) and fast-scan controlled adsorption voltammetry. These techniques allow us to probe the serotonergic system via measurement of evoked and ambient serotonin at carbon fiber microelectrodes (CFMs). Our data reveal no statistical differences, in the hippocampus, in female serotonin chemistry during the different stages of the estrous cycle compared to the mean female response. Furthermore, no difference was observed in evoked serotonin release and reuptake, nor ambient extracellular serotonin levels between male and female mice. We applied a previously developed mathematical model that fits our serotonin signals as a function of several synaptic processes that control the extracellular levels of this transmitter. We used the model to study potential system differences between males and females. One hypothesis brought fourth, that female mice exhibit tighter autoreceptor control of serotonin, is validated via literature and methiothepin challenge. We postulate that this tight regulation may act as a control mechanism against changes in the serotonin signal mediated by estrogen spikes. Importantly, this safety mechanism has no consequence for acutely administered escitalopram's (ESCIT's) ability to increase extracellular serotonin between the sexes. This work demonstrates little fundamental differences in in vivo hippocampal serotonin between the sexes, bar control mechanisms in female mice that can be observed under extraneous circumstances. We thus highlight the importance of considering sex as a biological factor in determining pharmacodynamics for personalized medical treatments that involve targeting serotonin receptors.

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Female hippocampal estrogens have a significant correlation with cyclic fluctuation of hippocampal spines.

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