Sex Differences in Hippocampal Estradiol-Induced N-Methyl-<i>D</i>-Aspartic Acid Binding and Ultrastructural Localization of Estrogen Receptor-Alpha

Abstract

Estradiol increases dendritic spine density and synaptogenesis in the CA1 region of the female hippocampus. This effect is specific to females, as estradiol-treated males fail to show increases in hippocampal spine density. Estradiol-induced spinogenesis in the female is dependent upon upregulation of the N-methyl-D-aspartic acid (NMDA) receptor as well as on non-nuclear estrogen receptors (ER), including those found in dendrites. Thus, in the male, the inability of estradiol to induce spinogenesis may be related to a failure of estradiol to increase hippocampal NMDA receptors as well as a paucity of dendritic ER. In the first experiment, we sought to investigate this possibility by assessing NMDA receptor binding, using [³H]-glutamate autoradiography, in estradiol-treated males and females. We found that while estradiol increases NMDA binding in gonadectomized females, estradiol fails to modulate NMDA binding in gonadectomized males. To further investigate sex differences in the hippocampus, we conducted a second separate, but related, ultrastructural study in which we quantified ERα-immunoreactivity (ERα-ir) in neuronal profiles in the CA1 region of the hippocampus in intact males and females in diestrus and proestrus. Consistent with previous reports in the female, we found ERα-ir in several extranuclear sites including dendrites, spines, terminals and axons. Statistical analyses revealed that females in proestrus had a 114.3% increase in ERα-labeled dendritic spines compared to females in diestrus and intact males. Taken together, these studies suggest that both the ability of estrogen to increase NMDA binding in the hippocampus and the presence of ERα in dendritic spines may contribute to the observed sex difference in estradiol-induced hippocampal spinogenesis.

Post-synaptic Density-95 (PSD-95) Binding Capacity of G-protein-coupled Receptor 30 (GPR30), an Estrogen Receptor That Can Be Identified in Hippocampal Dendritic Spines

“…Alongside our previous findings on the nonnuclear localization of estrogen receptor ␣ (ER␣) and ER␤ in dendritic spines (60,61), these data on GPR30 and spine localization may begin to provide an additional explanation on how E2 might modulate synaptic plasticity and non-genomic hormone effects in the hippocampus.…”

17‐β‐Estradiol‐mediated activation of extracellular‐signal regulated kinase, phosphatidylinositol 3‐kinase/protein kinase B‐Akt and N‐methyl‐d‐aspartate receptor phosphorylation in cortical synaptoneurosomes

“…Immunohistochemical studies using antibodies directed toward typical ERs (a or b) have shown the presence of estrogen receptors in mitochondria, endoplasmic reticulum, as well as in synaptic membranes (Blaustein et al 1992;Chen et al 2004;Revankar et al 2005;Romeo et al 2005). In these studies, the nature of the membrane-bound estrogen receptor has been proposed to resemble ERa (Razandi et al 2004;Acconcia et al 2005), and the identity of the ERb localized to membranes remains controversial (Yang et al 2004(Yang et al , 2006.…”

Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: Complexity of steroid hormone-growth factor interactions in the adult CNS

“…It also is likely that a consensus has been difficult because estrogen receptor (ER) localization changes with endocrine state. Thus, at proestrus, a different distribution of ERα was reported relative to other cycle stages [19,20]. Changes in ERs may also occur after estradiol treatment [21,22].…”

“…In addition, although one may question evidence of nuclear receptors, there is evidence of cytosolic receptors in diverse areas of granule cells using electron microscopy [19,23]. It is also important to bear in mind that, depending on the endocrine state, estrogen receptors may be more or less amenable to immunocytochemical evaluation [19,20], so they could be missed. And indeed the studies that show few estrogen receptors in granule cells were conducted at a time when they were least likely to be obvious, i.e.…”