Estrogen increases the number of spinophilin-immunoreactive spines in the hippocampus of young and aged female rhesus monkeys.
It is well documented that estrogen increases dendritic spine density in CA1 pyramidal cells of young female rats. However, this effect is attenuated in aged rats. We report here a quantitative analysis of estrogen effects on hippocampal spine number as visualized with antispinophilin in young (6-8 years old) and aged (19-23 years old) female rhesus monkeys, a species with a pattern of female endocrine senescence comparable to that of humans. Monkeys were ovariectomized and administered either vehicle or estradiol cypionate 3 months postovariectomy, followed by an additional dose 3 weeks later, with perfusion 24 hours after the last estrogen treatment. Immunolocalization of spinophilin, a spine-associated protein, was used for quantitative stereologic analyses of total spinophilin-immunoreactive spine numbers in CA1 stratum radiatum and the inner and outer molecular layers of dentate gyrus. In both young and aged female monkeys, the estrogen-treated groups had an increase in spinophilin-immunoreactive spines (37% in young, P <.005; 35% in aged, P <.05) compared with the untreated groups that amounted to more than 1 billion additional immunoreactive spines. The young group also showed a trend toward an estrogen-induced increase in immunoreactive spines in the dentate gyrus outer molecular layer, but this effect was not statistically significant (P =.097). We conclude that spine number in the rhesus monkey hippocampus is highly responsive to estrogen, yet, unlike the female rat, aged female rhesus monkeys retain the capacity for spine induction in response to estrogen. These data have important implications for cognitive effects of estrogen replacement in postmenopausal women and demonstrate that an estrogen replacement protocol that mimics normal physiological cycles with timed, intermittent peaks can have profound neurobiological effects.
Hao
Jiandong
J
Kastor Neurobiology of Aging Laboratories and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Janssen
William G M
WG
Tang
Yong
Y
Roberts
Jeffrey A
JA
McKay
Heather
H
Lasley
Bill
B
Allen
Patrick B
PB
Greengard
Paul
P
Rapp
Peter R
PR
Kordower
Jeffrey H
JH
Hof
Patrick R
PR
Morrison
John H
JH
D000367:Age Factors; D000818:Animals; D015415:Biomarkers; D003072:Cognition Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004334:Drug Administration Schedule; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D030762:Estrous Cycle / Q000187:drug effects / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D008253:Macaca mulatta / Q000033:anatomy & histology / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D010052:Ovariectomy; D017698:Postmenopause / Q000378:metabolism; D000099273:Neurabins
D015415:Biomarkers; D004967:Estrogens; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D000099273:Neurabins