Both Nuclear and Membrane Estrogen Receptor Alpha Impact the Expression of Estrogen Receptors and Plasticity Markers in the Mouse Hypothalamus and Hippocampus

SIMPLE SUMMARY: The diversity of membrane and nuclear estrogen receptor (ER) expression in the brain suggests numerous roles for estrogens throughout life. The aim of this study was to examine the effects of selective expression of membrane-only ERα (MOER) or nuclear-only ERα (NOER) on the distributions of proteins known to be involved in paraventricular hypothalamic nucleus (PVN) function and estrogen-mediated plasticity in the hippocampus. We found that, although the PVN has both membrane and nuclear ERα, only loss of nuclear ERα impacted ERβ expression. In hippocampal CA1, an area with primarily extranuclear ERα, and the dentate gyrus, which contains nuclear and extranuclear ERα and ERβ, a marker of plasticity (phosphorylated Trkb) changed with both membrane and nuclear receptor loss, but the direction of the change was region-specific. In the hippocampal dentate gyrus and CA3 regions, where there is less ERα expression overall, loss of nuclear or membrane ERα appeared to have less impact on plasticity markers. Altogether, this work generates new questions about the functions of membrane and nuclear ERs in the development of the brain and actions in adulthood. ABSTRACT: Estrogens via estrogen receptor alpha (ERα) genomic and nongenomic signaling can influence plasticity processes in numerous brain regions. Using mice that express nuclear only ERα (NOER) or membrane only ERα (MOER), this study examined the effect of receptor compartmentalization on the paraventricular nucleus of the hypothalamus (PVN) and the hippocampus. The absence of nuclear and membrane ERα expression impacted females but not males in these two brain areas. In the PVN, quantitative immunohistochemistry showed that the absence of nuclear ERα increased nuclear ERβ. Moreover, in the hippocampus CA1, immuno-electron microscopy revealed that the absence of either nuclear or membrane ERα decreased extranuclear ERα and pTrkB in synapses. In contrast, in the dentate gyrus, the absence of nuclear ERα increased pTrkB in synapses, whereas the absence of membrane ERα decreased pTrkB in axons. However, the absence of membrane only ERα decreased the sprouting of mossy fibers in CA3 as reflected by changes in zinc transporter immunolabeling. Altogether these findings support the idea that both membrane and nuclear ERα contribute overlapping and unique actions of estrogen that are tissue- and cellular-specific.