Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory.
Estrogens have long been implicated in influencing cognitive processes, yet the molecular mechanisms underlying these effects and the roles of the estrogen receptors alpha (ERalpha) and beta (ERbeta) remain unclear. Using pharmacological, biochemical and behavioral techniques, we demonstrate that the effects of estrogen on hippocampal synaptic plasticity and memory are mediated through ERbeta. Selective ERbeta agonists increased key synaptic proteins in vivo, including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ERbeta knockout mice. In hippocampal slices, ERbeta activation enhanced long-term potentiation, an effect that was absent in slices from ERbeta knockout mice. ERbeta activation induced morphological changes in hippocampal neurons in vivo, including increased dendritic branching and increased density of mushroom-type spines. An ERbeta agonist, but not an ERalpha agonist, also improved performance in hippocampus-dependent memory tasks. Our data suggest that activation of ERbeta can regulate hippocampal synaptic plasticity and improve hippocampus-dependent cognition.
Liu
Feng
F
Wyeth Research, Discovery Neuroscience, 865 Ridge Road, Monmouth Junction, New Jersey 08852, USA. liuf2@wyeth.com
Day
Mark
M
Muñiz
Luis C
LC
Bitran
Daniel
D
Arias
Robert
R
Revilla-Sanchez
Raquel
R
Grauer
Steve
S
Zhang
Guoming
G
Kelley
Cody
C
Pulito
Virginia
V
Sung
Amy
A
Mervis
Ronald F
RF
Navarra
Rachel
R
Hirst
Warren D
WD
Reinhart
Peter H
PH
Marquis
Karen L
KL
Moss
Stephen J
SJ
Pangalos
Menelas N
MN
Brandon
Nicholas J
NJ
D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000819:agonists / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D010052:Ovariectomy; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D047629:Estrogen Receptor beta; D004967:Estrogens; D004958:Estradiol