title: Cytoskeletal changes underlie estrogen's acute effects on synaptic transmission and plasticity.
abstract: Estrogen, in addition to its genomic effects in brain, causes rapid and reversible changes to synaptic operations. We report here that these acute actions are due to selective activation of an actin-signaling cascade normally used in the production of long-term potentiation (LTP). Estrogen, or a selective agonist of the steroid's beta-receptor, caused a modest increase in fast glutamatergic transmission and a pronounced facilitation of LTP in adult hippocampal slices; both effects were completely eliminated by latrunculin, a toxin that prevents actin filament assembly. Estrogen also increased spine concentrations of filamentous actin and strongly enhanced its polymerization in association with LTP. A search for the origins of these effects showed that estrogen activates the small GTPase RhoA and phosphorylates (inactivates) the actin severing protein cofilin, a downstream target of RhoA. Moreover, an antagonist of RhoA kinase (ROCK) blocked estrogen's synaptic effects. Estrogen thus emerges as a positive modulator of a RhoA>ROCK>LIM kinase>cofilin pathway that regulates the subsynaptic cytoskeleton. It does not, however, strongly affect a second LTP-related pathway, involving the GTPases Rac and Cdc42 and their effector p21-activated kinase, which may explain why its acute effects are reversible. Finally, ovariectomy depressed RhoA activity, spine cytoskeletal plasticity, and LTP, whereas brief infusions of estrogen rescued plasticity, suggesting that the deficits in plasticity arise from acute, as well as genomic, consequences of hormone loss.
authors.affiliation: Department of Psychiatry, University of California, Irvine, California 92697, USA.
authors.forename: Enikö A
authors.initials: EA
authors.lastname: Kramár
authors.forename: Lulu Y
authors.initials: LY
authors.lastname: Chen
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Rex
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Christine M
authors.initials: CM
authors.lastname: Gall
authors.forename: Gary
authors.initials: G
authors.lastname: Lynch
mesh_terms: D000199:Actins / Q000378:metabolism; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism*; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D000077267:Fulvestrant; D018756:GABA Antagonists / Q000494:pharmacology; D036145:Ginsenosides / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018613:Microscopy, Confocal; D009434:Neural Pathways / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010052:Ovariectomy / Q000379:methods; D010080:Oxazoles / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010636:Phenols / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012502:Sapogenins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D053778:Thiazolidines / Q000494:pharmacology
chemical_list: D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004958:Estradiol; D004965:Estrogen Antagonists; D004967:Estrogens; D018691:Excitatory Amino Acid Antagonists; D000077267:Fulvestrant; D018756:GABA Antagonists; D036145:Ginsenosides; D010080:Oxazoles; D010636:Phenols; D010852:Picrotoxin; D012502:Sapogenins; D053778:Thiazolidines; C502077:WAY 200070; C507965:ginsenoside 20S-protopanaxatriol; C037067:latrunculin A