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Cited by 264Neuroscience and Neuropharmacology ResearchEstrogen and related hormone effectsProtein Kinase Regulation and GTPase Signaling

Cytoskeletal changes underlie estrogen’s acute effects on synaptic transmission and plasticity.

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Kramár, Enikö A., Chen, Lulu Y., Brandon, Nicholas J., Rex, Christopher S., Liu, Feng, Gall, Christine M., Lynch, Gary·2009·The Journal of Neuroscience
DOI 10.1523/jneurosci.3059-09.2009PMC PMC2806054
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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 β-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.

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  • Modulation of cofilin activity has been directly linked with alteration in dendritic spine morphogenesis, synaptic transmission and plasticity.

    “Modulation of cofilin activity has been directly linked with alteration in dendritic spine morphogenesis, synaptic transmission and plasticity (Kramar et al., 2009; Shankar et al., 2007).”

    From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Kramar et al., 2009

    The Results (page not specified) report that estradiol increased cofilin phosphorylation and that blocking its upstream ROCK pathway eliminated estradiol-induced changes in synaptic transmission. The Discussion links cofilin phosphorylation and actin assembly to LTP, but treats effects on spine growth and retraction as a plausible explanation rather than directly demonstrating that cofilin modulation alters spine morphogenesis. (LLM, conf=0.84)

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Authors
Kramár, E. A., Chen, L. Y., Brandon, N. J., Rex, C. S., Liu, F., Gall, C. M., & Lynch, G.
Affiliations
  • University of California, Irvine (US)
  • Wyeth (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2009-10-14
Volume
29
Issue
41
Pages
12982-12993
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.3059-09.2009
PMC
PMC2806054
OpenAlex
W2002639930
Cited by
264
References
2
Citations by year
2026: 4 · 2025: 7 · 2024: 9 · 2023: 9 · 2022: 12 · 2021: 20 · 2020: 17 · 2019: 11 · 2018: 17 · 2017: 18 · 2016: 19 · 2015: 23 · 2014: 17 · 2013: 17 · 2012: 32
FWCI
8.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute of Mental Health (MH083396, F31MH083396)
  • National Institute of Neurological Disorders and Stroke (P01NS045260, NS045260, NS 045540, R01NS051823, NS051923, T32NS045540)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
estrogen, synaptic plasticity, long-term potentiation, actin cytoskeleton, RhoA, Rho kinase, cofilin, LIM kinase, hippocampus, dendritic spines, glutamatergic neurotransmission, estrogen receptor beta, ovariectomy, p21-activated kinase
MeSH terms
Fulvestrant, Actins, Age Factors, Analysis of Variance, Animals, Animals, Newborn, Biophysics, Cytoskeleton, Dose-Response Relationship, Drug, Electric Stimulation, Estradiol, Estrogen Antagonists, Estrogens, Female, Hippocampus, Male, Neural Pathways, Synaptic Transmission, Neuronal Plasticity, Neurons, Ovariectomy, Oxazoles, Phenols, Picrotoxin, Sapogenins, Signal Transduction, Rats, Sprague-Dawley, Long-Term Potentiation, Patch-Clamp Techniques, Microscopy, Confocal, Excitatory Amino Acid Antagonists, GABA Antagonists, Bridged Bicyclo Compounds, Heterocyclic, Excitatory Postsynaptic Potentials, Rats, Long-Evans, Ginsenosides, Dendritic Spines, Rats, Thiazolidines, In Vitro Techniques

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