Estrogen receptors, the hippocampus, and memory

Abstract

Estradiol effects on memory depend on hormone levels and the interaction of different estrogen receptors within neural circuits. Estradiol induces gene transcription and rapid membrane signaling mediated by estrogen receptor-alpha (ERα), estrogen receptor-beta (ERβ), and a recently characterized G-protein coupled estrogen receptor, each with distinct distributions and ability to influence estradiol-dependent signaling. Investigations using receptor specific agonists suggest that all three receptors rapidly activate kinase-signaling and have complex dose-dependent influences on memory. Research employing receptor knockout mice demonstrate that ERα maintains transcription and memory as estradiol levels decline. This work indicates a regulatory role of ERβ in transcription and cognition, which depends on estradiol levels and the function of ERα. The regulatory role of ERβ is due in part to ERβ acting as a negative regulator of ERα-mediated transcription. Vector-mediated expression of estrogen receptors in the hippocampus provides an innovative research approach and suggests that memory depends on the relative expression of ERα and ERβ interacting with estradiol levels. Notably, the ability of estradiol to improve cognition declines with advanced age along with decreased expression of estrogen receptors. Thus, it will be important for future research to determine the mechanisms that regulate estrogen receptor expression during aging.

Keywords: aging; estrogen; estrogen receptor-alpha (ERα); hippocampus; memory.

Figure 1

Dose–response function for 17β-estradiol (E2) effects on cognition. The relationship between the E2 dose and memory can be described by an inverted U function, such that ovariectomy and a low level of E2 result in poor memory. Memory is enhanced by increasing E2 to within the physiological range. Memory improvement is supplanted by impaired memory as E2 levels increase to supraphysiological levels.

Figure 2

Simplified models depicting rapid estrogen receptor signaling (left) and classical nuclear pathway (right). (A) In the rapid estrogen receptor signaling pathway, estrogen activates membrane associated estrogen receptors and associated G-protein coupled receptors to induce intracellular signaling cascades, which rapidly influence neuronal physiology or lead to the phosphorylation of the estrogen receptor-alpha (ERα) or CREB proteins. (B) In the classical pathway, estrogen binds to an inactive ERα or ERβ within the cytoplasm or the nucleus of the cell. The activated estrogen receptor monomer forms a dimer with another activated estrogen receptor monomer to create either a homodimer or a heterodimer, which then binds to an estrogen response element (ERE) within the DNA, along with other co-regulator proteins (not shown) to modify transcription of target genes. Note that ERα homodimers exhibit increased transcription relative to estrogen receptor heterodimers or ERβ homodimers because of ERβ acting as a negative regulator of ERα-mediated transcription.

Figure 3

Non-homologous domains/regions within human nuclear estrogen receptors (hERs) contribute to dissimilarities in transcription. Although ERα and ERβ are highly homologous (95%) within the DNA binding domain (DBD), ERα has greater transcriptional activity. Differences in the ligand binding domain (LBD) contribute to increased affinity of 17β-estradiol (E2) for ERα. Furthermore, differences in the structure of the activation function regions (AF-1 and AF-2) influence the ability of transcriptional co-regulators to interact with the receptors.

Figure 4

Role of estrogen receptor-alpha (ERα) and ERβ in transcription and cognition: studies using ERKO mice. (A) For ERβKO mice, the absence of ERβ results in a leftward shift in the descending arm of the dose–response curve. Ovariectomized ERβKO mice exhibit increased transcription of E2-sensitive genes and better cognition. Acute E2 treatment decreases transcription and fails to improve memory and chronic treatment impairs memory. (B) For ERαKO mice, the ascending arm of the dose response function for memory and 17β-estradiol (E2)- mediated transcription is shifted to the right. In this case, memory impairment is observed in low estrogen condition such as following ovariectomy and E2 treatment improves cognition and increases E2-sensitive transcription.

Figure 5

Post-translational regulation of estrogen receptor expression. Ligand-bound estrogen receptor-alpha (ERα)- mediated transcription is coupled with the Hsc70-interacting protein (CHIP) and ubiquination–proteolysis process, such that ligand-bound ERα is degraded following successful transcription of the target gene. In contrast, ERβ interacts with CHIP and ubiquination and subsequent ligand binding can induce transcription or transport to the proteasome for degradation. Thus, ligand-bound receptor degradation may indicate ongoing transcription for ERα or act to down-regulate ERβ transcriptional activity. Other posttranscriptional modifications include ERα miRNAs that bind to the 3′ untranslated region and prevent mRNA stability or translation.

Figure 6

Transcriptional regulation of estrogen receptor expression. The promoter region of the estrogen receptoralpha (ERα) gene (ESR1) contains CpG sites and methylation within this region is associated with reduced transcription of ESR1. Successful transcription requires histone acetyltransferase (HAT) enzyme activity to increase access to DNA for transcription. Histone deacetylases (HDACs) prevent the unwinding of the DNA from the histone thereby preventing transcription.