Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors alpha and beta.
Neurogenesis persists throughout life under normal and degenerative conditions. The adult subventricular zone (SVZ) generates neural stem cells capable of differentiating to neuroblasts and migrating to the site of injury in response to brain insults. In the present study, we investigated whether estradiol increases neurogenesis in the SVZ in an animal model of stroke to potentially promote the ability of the brain to undergo repair. Ovariectomized C57BL/6J mice were implanted with capsules containing either vehicle or 17beta-estradiol, and 1 week later they underwent experimental ischemia. We utilized double-label immunocytochemistry to identify the phenotype of newborn cells (5-bromo-2'-deoxyuridine-labeled) with various cellular markers; doublecortin and PSA-NCAM as the early neuronal marker, NeuN to identify mature neurons, and glial fibrillary acidic protein to identify astrocytes. We report that low physiological levels of estradiol treatment, which exert no effect in the uninjured state, significantly increase the number of newborn neurons in the SVZ following stroke injury. This effect of estradiol is limited to the dorsal region of the SVZ and is absent from the ventral SVZ. The proliferative actions of estradiol are confined to neuronal precursors and do not influence gliosis. Furthermore, we show that both estrogen receptors alpha and beta play pivotal functional roles, insofar as knocking out either of these receptors blocks the ability of estradiol to increase neurogenesis. These findings clearly demonstrate that estradiol stimulates neurogenesis in the adult SVZ, thus potentially facilitating the brain to remodel and repair after injury.
Suzuki
Shotaro
S
Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, California 95616, USA.
Gerhold
Lynnette M
LM
Böttner
Martina
M
Rau
Shane W
SW
Dela Cruz
Christopher
C
Yang
Enhua
E
Zhu
Hong
H
Yu
Jin
J
Cashion
Adrienne B
AB
Kindy
Mark S
MS
Merchenthaler
Istvan
I
Gage
Fred H
FH
Wise
Phyllis M
PM
D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002552:Cerebral Ventricles / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D016555:Matched-Pair Analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D020521:Stroke / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D018696:Neuroprotective Agents; D004958:Estradiol