Estradiol Replacement Alters Expression of Genes Related to Neurotransmission and Immune Surveillance in the Frontal Cortex of Middle-Aged, Ovariectomized Rats

Estradiol (E2) modulates a wide range of functions of the frontal cerebral cortex. From the onset of menopause, declining levels of E2 can cause cognitive disturbances and changes in behavior that can be counterbalanced by hormone replacement. To study the effect of E2 replacement on the cortical transcriptome in a rodent model with low serum E2 level, we treated middle-aged, ovariectomized rats with E2 or vehicle using osmotic minipumps for 4 wk. Six animals for each group were selected, and samples of their frontal cortex were subjected to expression profiling using oligonucleotide microarrays. The explored E2-regulated genes were related to neurotransmission (Adora2a, Cartpt, Drd1a, Drd2, Gjb2, Nts, and Tac1), immunity (C3, C4b, Cd74, Fcgr2b, Mpeg1, and RT1-Aw2), signal transduction (Igf2, Igfbp2, Igfbp6, Rgs9, and Sncg), transport (Abca1, Hba-a2, Slc13a3, and Slc22a8), extracellular matrix (Col1a2, Col3a1, Fmod, and Lum), and transcription (Irf7 and Nupr1). Seventy-four percent of the transcriptional changes identified by microarray were confirmed by quantitative real-time PCR. The genes identified by expression profiling indicated that chronic E2 replacement significantly altered the transcriptome of the frontal cortex. The genomic effects of E2 influenced dopaminergic and peptidergic neurotransmission, immune surveillance, adenosine and insulin-like growth factor signaling and transport processes, among other functions. Identification of these novel E2-regulated mechanisms highlights the wide range of genomic responses of the aging female frontal cerebral cortex subjected to hormone replacement. Some of the genomic effects identified in this study may underlie the beneficial effects of E2 on cognition, behavior, and neuroprotection.