The effects of acute 17β-estradiol treatment on gene expression in the young female mouse hippocampus

Abstract

Previous studies have demonstrated that treatment with 17β-estradiol (E 2 ) improves both spatial and nonspatial memory in young female mice. Still unclear, however, are the molecular mechanisms underlying the beneficial effects of E 2 on memory. We have previously demonstrated that a single post-training intraperitoneal (i.p.) injection of 0.2 mg/kg E 2 can enhance hippocampal-dependent spatial and object memory consolidation (e.g., Gresack and Frick, 2006b). Therefore, in the present study, we performed a microarray analysis on the dorsal hippocampi of 4 month-old female mice injected i.p. with vehicle or 0.2 mg/kg E 2 . Genes were considered differentially expressed following E 2 treatment if they showed a greater than two-fold change in RNA expression levels compared to controls. Overall, out of a total of approximately 25,000 genes represented on the array, 204 genes showed altered mRNA expression levels upon E 2 treatment, with 111 up-regulated and 93 downregulated. Of these, 17 of the up-regulated and 6 of the down-regulated genes are known to be involved in learning and memory. mRNA expression changes in 5 of the genes were confirmed by real-time quantitative PCR analysis, and protein changes in these same genes were confirmed by Western blot analysis: Hsp70, a heat shock protein known to be estrogen responsive; Igfbp2, an IGF-I binding protein; Actn4, an actin binding protein involved in protein trafficking; Tubb2a, the major component of microtubules; and Snap25, a synaptosome-specific protein required for neurotransmitter release. The types of genes altered indicate that E 2 may induce changes in the structural mechanics of cells within the dorsal hippocampus that could be conducive to promoting memory consolidation.

Estrogen promotes learning-related plasticity by modifying the synaptic cytoskeleton

“…While there is almost no information on how the acute effects reviewed above relate to, or interact with, the genomic actions of estrogen as found in the periphery (Carroll et al, 2006), there are reasons to suspect that links exist (Pechenino and Frick, 2009; Aenlle and Foster, 2010). The LTP related actin signaling initiated by E2 is reported to engage translational activity by dendritic ribosomes via mechanisms that also stimulate transcription (Smart et al, 2003).…”

Molecular mechanisms underlying the memory-enhancing effects of estradiol

“…Thus, the E 2 -induced activation of ERK in the hippocampus likely leads to gene transcription. Numerous studies have shown that gene expression is altered in the hippocampus after E 2 treatment (Aenlle and Foster, 2010; Aenlle et al, 2009; Noriega et al, 2010; Pechenino and Frick, 2009), although it is unclear if this is a direct result of CREB phosphorylation.…”

Epigenetic regulation of estrogen-dependent memory

“…As will be discussed below, E 2 also rapidly activates numerous cell-signaling cascades in the hippocampus that are essential for long-term memory formation (Zhao and Brinton, 2007; Frick, 2012). The activation of these signaling pathways influences hippocampal histone acetylation, gene expression, and protein synthesis in the hippocampus (Pechenino and Frick, 2009; Zhao et al, 2010; Fortress et al, 2013), although it remains unclear whether these changes promote synaptogenesis and neurogenesis. Such rapid changes in hippocampal morphology may be possible, given that activation of Rap/AF-6/ERK1/2 signaling by E 2 promotes the formation of new dendritic spines in mature cultured cortical neurons (Srivastava et al, 2008).…”