Ovariectomy Alters Gene Expression of the Hippocampal Formation in Middle-Aged Rats

Ovarian hormones regulate the transcriptome of the hippocampus and modulate its functions. During menopause this complex signaling declines, leading to impaired learning and memory. This study was undertaken to clarify the effects of long-term, surgical ovariectomy (OVX) on the rat hippocampal transcriptome. At age of 13 months, intact control and ovariectomized groups were formed. All animals were killed 5 weeks after gonadectomy; hippocampal formations were dissected and processed for transcriptome analysis. Microarray and polymerase chain reaction studies identified 252 and 61 genes, respectively, whose expression was altered in the lack of ovarian hormones. Pathway analysis revealed impact on neuroactive ligand-receptor interaction, endocannabinoid, and estrogen signaling, among others. Network and interaction analyses of proteins encoded by OVX-regulated genes revealed upregulation of growth/troph/transcription factor signaling assembly (Mdk, Fgf1, Igf2, Ngf, Ngfr, Ntf3, Ntrk1, Otx2, Hif1a, Esr1, Nr4a3), peptides/peptide receptors (Cartpt, Kl, Ttr, Gnrhr), neurotransmission (Grm1, Gria4, Gls, Slc18a2, Kcnj6), and genes serving immune functions (C3, Ccl2, Itgam, Il1b). Downregulated clusters included neuropeptides and their receptors (Adcyap1, Cbln2, Cck, Cckbr, Crhr1 and 2, Oprd1, Nts, Penk, Sstr1, Vip), neurotransmitter signaling (Htr2c, Chrna3, Chrm4, Grm8, Hrh3, Slc17a6), and potassium channels (Kcnk9, Kcnj9, Kcnma1, Kcnc2). Several transcription factors (Rxra, Thrb), solute carriers and defense molecules (Apitd1, Bcl2, C1ql3, Ilr3a, Sod1, Sncb) also underwent downregulation. The findings indicate that surgical gonadectomy carried out at middle-age robustly changes the hippocampal transcriptome that alters neurogenesis, synaptic plasticity, immune modulation, causing cognitive dysfunctions.