Abstract
Dendritic spines undergo actin-based growth and shrinkage during synaptic plasticity, in which the actin depolymerizing factor (ADF)/cofilin family of actin-associated proteins are important. Elevated ADF/cofilin activities often lead to reduced spine size and immature spine morphology but can also enhance synaptic potentiation in some cases. Thus, ADF/cofilin may have distinct effects on postsynaptic structure and function. We found that ADF/cofilin-mediated actin dynamics regulated AMPA receptor (AMPAR) trafficking during synaptic potentiation, which was distinct from actin's structural role in spine morphology. Specifically, elevated ADF/cofilin activity markedly enhanced surface addition of AMPARs after chemically induced long-term potentiation (LTP), whereas inhibition of ADF/cofilin abolished AMPAR addition. We found that chemically induced LTP elicited a temporal sequence of ADF/cofilin dephosphorylation and phosphorylation that underlies AMPAR trafficking and spine enlargement. These findings suggest that temporally regulated ADF/cofilin activities function in postsynaptic modifications of receptor number and spine size during synaptic plasticity.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bredt, D.S. & Nicoll, R.A. AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379 (2003).
Collingridge, G.L., Isaac, J.T. & Wang, Y.T. Receptor trafficking and synaptic plasticity. Nat. Rev. Neurosci. 5, 952–962 (2004).
Malinow, R. & Malenka, R.C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).
Song, I. & Huganir, R.L. Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci. 25, 578–588 (2002).
Yuste, R. & Bonhoeffer, T. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu. Rev. Neurosci. 24, 1071–1089 (2001).
Nimchinsky, E.A., Sabatini, B.L. & Svoboda, K. Structure and function of dendritic spines. Annu. Rev. Physiol. 64, 313–353 (2002).
Segal, M. Dendritic spines and long-term plasticity. Nat. Rev. Neurosci. 6, 277–284 (2005).
Matsuzaki, M., Honkura, N., Ellis-Davies, G.C. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766 (2004).
Park, M. et al. Plasticity-induced growth of dendritic spines by exocytic trafficking from recycling endosomes. Neuron 52, 817–830 (2006).
Tada, T. & Sheng, M. Molecular mechanisms of dendritic spine morphogenesis. Curr. Opin. Neurobiol. 16, 95–101 (2006).
Cingolani, L.A. & Goda, Y. Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nat. Rev. Neurosci. 9, 344–356 (2008).
Hotulainen, P. & Hoogenraad, C.C. Actin in dendritic spines: connecting dynamics to function. J. Cell Biol. 189, 619–629 (2010).
Bernstein, B.W. & Bamburg, J.R. ADF/cofilin: a functional node in cell biology. Trends Cell Biol. 20, 187–195 (2010).
Van Troys, M. et al. Ins and outs of ADF/cofilin activity and regulation. Eur. J. Cell Biol. 87, 649–667 (2008).
Rex, C.S. et al. Different Rho GTPase–dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J. Cell Biol. 186, 85–97 (2009).
Zhou, Q., Homma, K.J. & Poo, M.M. Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44, 749–757 (2004).
Chen, L.Y., Rex, C.S., Casale, M.S., Gall, C.M. & Lynch, G. Changes in synaptic morphology accompany actin signaling during LTP. J. Neurosci. 27, 5363–5372 (2007).
Meng, Y. et al. Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35, 121–133 (2002).
Sankaranarayanan, S., De Angelis, D., Rothman, J.E. & Ryan, T.A. The use of pHluorins for optical measurements of presynaptic activity. Biophys. J. 79, 2199–2208 (2000).
Lin, D.T. & Huganir, R.L. PICK1 and phosphorylation of the glutamate receptor 2 (GluR2) AMPA receptor subunit regulates GluR2 recycling after NMDA receptor–induced internalization. J. Neurosci. 27, 13903–13908 (2007).
Takumi, Y., Ramirez-Leon, V., Laake, P., Rinvik, E. & Ottersen, O.P. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat. Neurosci. 2, 618–624 (1999).
Aniksztejn, L. & Ben-Ari, Y. Novel form of long-term potentiation produced by a K+ channel blocker in the hippocampus. Nature 349, 67–69 (1991).
Ashby, M.C., Maier, S.R., Nishimune, A. & Henley, J.M. Lateral diffusion drives constitutive exchange of AMPA receptors at dendritic spines and is regulated by spine morphology. J. Neurosci. 26, 7046–7055 (2006).
Allison, D.W., Gelfand, V.I., Spector, I. & Craig, A.M. Role of actin in anchoring postsynaptic receptors in cultured hippocampal neurons: differential attachment of NMDA versus AMPA receptors. J. Neurosci. 18, 2423–2436 (1998).
Bubb, M.R., Senderowicz, A.M., Sausville, E.A., Duncan, K.L. & Korn, E.D. Jasplakinolide, a cytotoxic natural product, induces actin polymerization and competitively inhibits the binding of phalloidin to F-actin. J. Biol. Chem. 269, 14869–14871 (1994).
Aizawa, H. et al. Phosphorylation of cofilin by LIM kinase is necessary for semaphorin 3A–induced growth cone collapse. Nat. Neurosci. 4, 367–373 (2001).
Heredia, L. et al. Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid beta–induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer's disease. J. Neurosci. 26, 6533–6542 (2006).
Aunis, D. & Bader, M.F. The cytoskeleton as a barrier to exocytosis in secretory cells. J. Exp. Biol. 139, 253–266 (1988).
Eitzen, G. Actin remodeling to facilitate membrane fusion. Biochim. Biophys. Acta 1641, 175–181 (2003).
Lanzetti, L. Actin in membrane trafficking. Curr. Opin. Cell Biol. 19, 453–458 (2007).
Spector, I., Shochet, N.R., Kashman, Y. & Groweiss, A. Latrunculins: novel marine toxins that disrupt microfilament organization in cultured cells. Science 219, 493–495 (1983).
Kim, C.H. & Lisman, J.E. A role of actin filament in synaptic transmission and long-term potentiation. J. Neurosci. 19, 4314–4324 (1999).
Hotulainen, P. et al. Defining mechanisms of actin polymerization and depolymerization during dendritic spine morphogenesis. J. Cell Biol. 185, 323–339 (2009).
Racz, B. & Weinberg, R.J. Spatial organization of cofilin in dendritic spines. Neuroscience 138, 447–456 (2006).
Makino, H. & Malinow, R. AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron 64, 381–390 (2009).
Heine, M. et al. Surface mobility of postsynaptic AMPARs tunes synaptic transmission. Science 320, 201–205 (2008).
Rust, M.B. et al. Learning, AMPA receptor mobility and synaptic plasticity depend on n-cofilin–mediated actin dynamics. EMBO J. 29, 1889–1902 (2010).
Han, L. et al. Direct stimulation of receptor-controlled phospholipase D1 by phospho-cofilin. EMBO J. 26, 4189–4202 (2007).
Fukazawa, Y. et al. Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron 38, 447–460 (2003).
Okamoto, K., Nagai, T., Miyawaki, A. & Hayashi, Y. Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Nat. Neurosci. 7, 1104–1112 (2004).
Yuen, E.Y., Liu, W., Kafri, T., van Praag, H. & Yan, Z. Regulation of AMPA receptor channels and synaptic plasticity by cofilin phosphatase slingshot in cortical neurons. J. Physiol. 588, 2361–2371 (2010).
Onuma, H. et al. A calcineurin inhibitor, FK506, blocks voltage-gated calcium channel-dependent LTP in the hippocampus. Neurosci. Res. 30, 313–319 (1998).
Wang, Z. et al. Myosin Vb mobilizes recycling endosomes and AMPA receptors for postsynaptic plasticity. Cell 135, 535–548 (2008).
Schulz, T.W. et al. Actin/alpha-actinin–dependent transport of AMPA receptors in dendritic spines: role of the PDZ-LIM protein RIL. J. Neurosci. 24, 8584–8594 (2004).
Lee, C.W. et al. Regulation of acetylcholine receptor clustering by ADF/cofilin-directed vesicular trafficking. Nat. Neurosci. 12, 848–856 (2009).
Hoogenraad, C.C., Akhmanova, A., Galjart, N. & De Zeeuw, C.I. LIMK1 and CLIP-115: linking cytoskeletal defects to Williams syndrome. Bioessays 26, 141–150 (2004).
Campbell, R.E. et al. A monomeric red fluorescent protein. Proc. Natl. Acad. Sci. USA 99, 7877–7882 (2002).
Flynn, K.C., Pak, C.W., Shaw, A.E., Bradke, F. & Bamburg, J.R. Growth cone-like waves transport actin and promote axonogenesis and neurite branching. Dev. Neurobiol. 69, 761–779 (2009).
Deng, L. et al. Sequential postsynaptic maturation governs the temporal order of GABAergic and glutamatergic synaptogenesis in rat embryonic cultures. J. Neurosci. 27, 10860–10869 (2007).
Schafer, D.A. et al. Visualization and molecular analysis of actin assembly in living cells. J. Cell Biol. 143, 1919–1930 (1998).
Acknowledgements
This research was supported by grants from the US National Institutes of Health to J.Q.Z. (GM083889 GM084363, and HD023315), J.R.B. (NS40371), G.C. (NS054858) and H.C.H. (EY014852 and GM60448).
Author information
Authors and Affiliations
Contributions
J.G. performed a majority of the experiments on SEP-GluR1 insertion, C.W.L. contributed to the data on actin dynamics and Y.F. investigated cofilin phosphorylation and its contribution to spine size changes. D.K. performed the initial work on SEP-GluR1 imaging and cofilin regulation. X.T., C.S. and G.C. provided a majority of the electrophysiology data. K.Y. and H.C.H. contributed to the electrophysiological recordings on neurons expressing cofilin mutants. J.R.B. provided all of the cofilin reagents and insights into cofilin mechanisms and functions. J.Q.Z. designed, planned and guided the project and contributed to the image analysis.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–9 (PDF 1662 kb)
Rights and permissions
About this article
Cite this article
Gu, J., Lee, C., Fan, Y. et al. ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity. Nat Neurosci 13, 1208–1215 (2010). https://doi.org/10.1038/nn.2634
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn.2634
This article is cited by
-
The Coordinating Role of the Actin Cytoskeleton in Short-Term Neural Network Plasticity Involving Excitatory and Inhibitory Synapses
Neuroscience and Behavioral Physiology (2024)
-
Cyclin Y regulates spatial learning and memory flexibility through distinct control of the actin pathway
Molecular Psychiatry (2023)
-
Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit
Neurology and Therapy (2023)
-
Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1
Cell Death & Disease (2022)
-
Muskelin regulates actin-dependent synaptic changes and intrinsic brain activity relevant to behavioral and cognitive processes
Communications Biology (2022)