Abstract
Estradiol (E2) robustly activates transcription of a broad array of genes in the hippocampal formation of middle-aged ovariectomized rats via estrogen receptors (ERα, ERβ, and G protein-coupled ER). Selective ERβ agonists also influence hippocampal functions, although their downstream molecular targets and mechanisms are not known. In this study, we explored the effects of long-term treatment with ERβ agonist diarylpropionitrile (DPN, 0.05 mg/kg/day, sc.) on the hippocampal transcriptome in ovariectomized, middle-aged (13 month) rats. Isolated hippocampal formations were analyzed by Affymetrix oligonucleotide microarray and quantitative real-time PCR. Four hundred ninety-seven genes fulfilled the absolute fold change higher than 2 (FC > 2) selection criterion. Among them 370 genes were activated. Pathway analysis identified terms including glutamatergic and cholinergic synapse, RNA transport, endocytosis, thyroid hormone signaling, RNA degradation, retrograde endocannabinoid signaling, and mRNA surveillance. PCR studies showed transcriptional regulation of 58 genes encoding growth factors (Igf2, Igfb2, Igf1r, Fgf1, Mdk, Ntf3, Bdnf), transcription factors (Otx2, Msx1), potassium channels (Kcne2), neuropeptides (Cck, Pdyn), peptide receptors (Crhr2, Oprm1, Gnrhr, Galr2, Sstr1, Sstr3), neurotransmitter receptors (Htr1a, Htr2c, Htr2a, Gria2, Gria3, Grm5, Gabra1, Chrm5, Adrb1), and vesicular neurotransmitter transporters (Slc32a1, Slc17a7). Protein-protein interaction analysis revealed networking of clusters associated with the regulation of growth/troph factor signaling, transcription, translation, neurotransmitter and neurohormone signaling mechanisms and potassium channels. Collectively, the results reveal the contribution of ERβ-mediated processes to the regulation of transcription, translation, neurogenesis, neuromodulation, and neuroprotection in the hippocampal formation of ovariectomized, middle-aged rats and elucidate regulatory channels responsible for DPN-altered functional patterns. These findings support the notion that selective activation of ERβ may be a viable approach for treating the neural symptoms of E2 deficiency in menopause.
Highlights
17β-estradiol (E2) exerts profound effects in the brain including the hippocampus (Gould et al, 1990)
Microarray Study Differential expression was studied in the hippocampal formation by comparing vehicle- and ERβ agonist-treated animals
We found that chronic treatment with DPN evoked significant changes in the transcriptome
Summary
17β-estradiol (E2) exerts profound effects in the brain including the hippocampus (Gould et al, 1990). E2 improves cognitive performance in adult and middle-aged ovariectomized (OVX) rats (Talboom et al, 2008; Rodgers et al, 2010) and mice (Walf et al, 2008) These effects are mediated by the two canonical intracellular receptors ERα, ERβ, and the membrane G protein-coupled estrogen receptor GPER, which are expressed in the hippocampal formation (Shughrue and Merchenthaler, 2000; Brailoiu et al, 2007; Mitterling et al, 2010; Waters et al, 2015). Behavioral studies have shown that DPN evokes anxiolytic effects (Walf and Frye, 2005) and enhances performance in hippocampus-dependent memory tasks (Rhodes and Frye, 2006; Pisani et al, 2016). The present study was devoted to the aforementioned concept with the main task to determine whether long-term DPN treatment of middleaged OVX rats has an impact on the hippocampal transcriptome and to elucidate the putative cellular mechanisms and regulatory channels involved
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