Hippocampal Gene Expression Is Highly Responsive to Estradiol Replacement in Middle-Aged Female Rats.
In the hippocampus, estrogens are powerful modulators of neurotransmission, synaptic plasticity and neurogenesis. In women, menopause is associated with increased risk of memory disturbances, which can be attenuated by timely estrogen therapy. In animal models of menopause, 17β-estradiol (E2) replacement improves hippocampus-dependent spatial memory. Here, we explored the effect of E2 replacement on hippocampal gene expression in a rat menopause model. Middle-aged ovariectomized female rats were treated continuously for 29 days with E2, and then, the hippocampal transcriptome was investigated with Affymetrix expression arrays. Microarray data were analyzed by Bioconductor packages and web-based softwares, and verified with quantitative PCR. At standard fold change selection criterion, 156 genes responded to E2. All alterations but 4 were transcriptional activation. Robust activation (fold change > 10) occurred in the case of transthyretin, klotho, claudin 2, prolactin receptor, ectodin, coagulation factor V, Igf2, Igfbp2, and sodium/sulfate symporter. Classification of the 156 genes revealed major groups, including signaling (35 genes), metabolism (31 genes), extracellular matrix (17 genes), and transcription (16 genes). We selected 33 genes for further studies, and all changes were confirmed by real-time PCR. The results suggest that E2 promotes retinoid, growth factor, homeoprotein, neurohormone, and neurotransmitter signaling, changes metabolism, extracellular matrix composition, and transcription, and induces protective mechanisms via genomic effects. We propose that these mechanisms contribute to effects of E2 on neurogenesis, neural plasticity, and memory functions. Our findings provide further support for the rationale to develop safe estrogen receptor ligands for the maintenance of cognitive performance in postmenopausal women.
Laboratory of Endocrine Neurobiology (M.S., I.K., E.H., C.V., Z.L.), Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary; Faculty of Information Technology and Bionics (I.K., Z.L.), Pázmány Péter Catholic University, 1083 Budapest, Hungary; Faculty of Veterinary Science (N.S.), Szent István University, 1078 Budapest, Hungary; Functional Genomics Core (A.R.), Institute for Research in Biomedicine, 08028 Barcelona, Spain; and Functional Genomics Consulting (H.A.), 08780 Palleja, Spain.
Miklós
M
Sárvári
Laboratory of Endocrine Neurobiology (M.S., I.K., E.H., C.V., Z.L.), Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary; Faculty of Information Technology and Bionics (I.K., Z.L.), Pázmány Péter Catholic University, 1083 Budapest, Hungary; Faculty of Veterinary Science (N.S.), Szent István University, 1078 Budapest, Hungary; Functional Genomics Core (A.R.), Institute for Research in Biomedicine, 08028 Barcelona, Spain; and Functional Genomics Consulting (H.A.), 08780 Palleja, Spain.
Imre
I
Kalló
Laboratory of Endocrine Neurobiology (M.S., I.K., E.H., C.V., Z.L.), Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary; Faculty of Information Technology and Bionics (I.K., Z.L.), Pázmány Péter Catholic University, 1083 Budapest, Hungary; Faculty of Veterinary Science (N.S.), Szent István University, 1078 Budapest, Hungary; Functional Genomics Core (A.R.), Institute for Research in Biomedicine, 08028 Barcelona, Spain; and Functional Genomics Consulting (H.A.), 08780 Palleja, Spain.
Erik
E
Hrabovszky
Laboratory of Endocrine Neurobiology (M.S., I.K., E.H., C.V., Z.L.), Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary; Faculty of Information Technology and Bionics (I.K., Z.L.), Pázmány Péter Catholic University, 1083 Budapest, Hungary; Faculty of Veterinary Science (N.S.), Szent István University, 1078 Budapest, Hungary; Functional Genomics Core (A.R.), Institute for Research in Biomedicine, 08028 Barcelona, Spain; and Functional Genomics Consulting (H.A.), 08780 Palleja, Spain.
Norbert
N
Solymosi
Laboratory of Endocrine Neurobiology (M.S., I.K., E.H., C.V., Z.L.), Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary; Faculty of Information Technology and Bionics (I.K., Z.L.), Pázmány Péter Catholic University, 1083 Budapest, Hungary; Faculty of Veterinary Science (N.S.), Szent István University, 1078 Budapest, Hungary; Functional Genomics Core (A.R.), Institute for Research in Biomedicine, 08028 Barcelona, Spain; and Functional Genomics Consulting (H.A.), 08780 Palleja, Spain.
Annie
A
Rodolosse
Laboratory of Endocrine Neurobiology (M.S., I.K., E.H., C.V., Z.L.), Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary; Faculty of Information Technology and Bionics (I.K., Z.L.), Pázmány Péter Catholic University, 1083 Budapest, Hungary; Faculty of Veterinary Science (N.S.), Szent István University, 1078 Budapest, Hungary; Functional Genomics Core (A.R.), Institute for Research in Biomedicine, 08028 Barcelona, Spain; and Functional Genomics Consulting (H.A.), 08780 Palleja, Spain.
Csaba
C
Vastagh
Laboratory of Endocrine Neurobiology (M.S., I.K., E.H., C.V., Z.L.), Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary; Faculty of Information Technology and Bionics (I.K., Z.L.), Pázmány Péter Catholic University, 1083 Budapest, Hungary; Faculty of Veterinary Science (N.S.), Szent István University, 1078 Budapest, Hungary; Functional Genomics Core (A.R.), Institute for Research in Biomedicine, 08028 Barcelona, Spain; and Functional Genomics Consulting (H.A.), 08780 Palleja, Spain.
Herbert
H
Auer
Laboratory of Endocrine Neurobiology (M.S., I.K., E.H., C.V., Z.L.), Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary; Faculty of Information Technology and Bionics (I.K., Z.L.), Pázmány Péter Catholic University, 1083 Budapest, Hungary; Faculty of Veterinary Science (N.S.), Szent István University, 1078 Budapest, Hungary; Functional Genomics Core (A.R.), Institute for Research in Biomedicine, 08028 Barcelona, Spain; and Functional Genomics Consulting (H.A.), 08780 Palleja, Spain.
Zsolt
Z
Liposits
D000818:Animals; D027682:Cation Transport Proteins / Q000187:drug effects / Q000235:genetics; D057167:Claudins / Q000187:drug effects / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000494:pharmacology*; D005165:Factor V / Q000187:drug effects / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D005966:Glucuronidase / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects*; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000187:drug effects / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000187:drug effects / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D000090265:Klotho Proteins; D008593:Menopause / Q000187:drug effects*; D023421:Models, Animal; D011228:Prealbumin / Q000187:drug effects / Q000235:genetics; D011506:Proteins / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011981:Receptors, Prolactin / Q000187:drug effects / Q000235:genetics; D000077003:Sodium Sulfate Cotransporter; D027981:Symporters / Q000187:drug effects / Q000235:genetics
D027682:Cation Transport Proteins; D057167:Claudins; C491874:Cldn2 protein, rat; D004967:Estrogens; C000599313:Igf2 protein, rat; D018971:Insulin-Like Growth Factor Binding Protein 2; D047908:Intracellular Signaling Peptides and Proteins; D011228:Prealbumin; D011506:Proteins; D012333:RNA, Messenger; D011981:Receptors, Prolactin; D000077003:Sodium Sulfate Cotransporter; C473906:Sostdc1 protein, rat; D027981:Symporters; D004958:Estradiol; D007335:Insulin-Like Growth Factor II; D005165:Factor V; D005966:Glucuronidase; D000090265:Klotho Proteins