Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

MEF2 negatively regulates learning-induced structural plasticity and memory formation

Nature Neuroscience volume 15, pages 1255–1264 (2012)Cite this article

Subjects

Abstract

Memory formation is thought to be mediated by dendritic-spine growth and restructuring. Myocyte enhancer factor 2 (MEF2) restricts spine growth in vitro, suggesting that this transcription factor negatively regulates the spine remodeling necessary for memory formation. Here we show that memory formation in adult mice was associated with changes in endogenous MEF2 levels and function. Locally and acutely increasing MEF2 function in the dentate gyrus blocked both learning-induced increases in spine density and spatial-memory formation. Increasing MEF2 function in amygdala disrupted fear-memory formation. We rescued MEF2-induced memory disruption by interfering with AMPA receptor endocytosis, suggesting that AMPA receptor trafficking is a key mechanism underlying the effects of MEF2. In contrast, decreasing MEF2 function in dentate gyrus and amygdala facilitated the formation of spatial and fear memory, respectively. These bidirectional effects indicate that MEF2 is a key regulator of plasticity and that relieving the suppressive effects of MEF2-mediated transcription permits memory formation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Memory formation was associated with inhibitory phosphorylation of MEF2 and a decrease in amount of MEF2 protein.
Figure 2: Increasing MEF2 function during training impaired formation of spatial memory.
Figure 3: Increasing MEF2 function blocked spine growth associated with memory formation.
Figure 4: Increasing MEF2 function after training impaired memory incubation.
Figure 5: Overexpressing MEF2 in the lateral amygdala blocked long-term memory formation for contextual and cued fear conditioning.
Figure 6: Disrupting MEF2 function permitted robust memory formation after weak training.
Figure 7: Memory disruption produced by increasing MEF2 rescued by disrupting AMPAR endocytosis.

Similar content being viewed by others

References

  1. Bailey, C.H. & Kandel, E.R. Structural changes accompanying memory storage. Annu. Rev. Physiol. 55, 397–426 (1993).

    Article  CAS  Google Scholar 

  2. Harris, K.M. & Stevens, J.K. Dendritic spines of rat cerebellar Purkinje cells: serial electron microscopy with reference to their biophysical characteristics. J. Neurosci. 8, 4455–4469 (1988).

    Article  CAS  Google Scholar 

  3. Nimchinsky, E.A., Sabatini, B.L. & Svoboda, K. Structure and function of dendritic spines. Annu. Rev. Physiol. 64, 313–353 (2002).

    Article  CAS  Google Scholar 

  4. Alberini, C.M. Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev. 89, 121–145 (2009).

    Article  CAS  Google Scholar 

  5. Abel, T., Martin, K.C., Bartsch, D. & Kandel, E.R. Memory suppressor genes: inhibitory constraints on the storage of long-term memory. Science 279, 338–341 (1998).

    Article  CAS  Google Scholar 

  6. Flavell, S.W. et al. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311, 1008–1012 (2006).

    Article  CAS  Google Scholar 

  7. Barbosa, A.C. et al. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proc. Natl. Acad. Sci. USA 105, 9391–9396 (2008).

    Article  CAS  Google Scholar 

  8. Pulipparacharuvil, S. et al. Cocaine regulates MEF2 to control synaptic and behavioral plasticity. Neuron 59, 621–633 (2008).

    Article  CAS  Google Scholar 

  9. Lyons, G.E., Micales, B.K., Schwarz, J., Martin, J.F. & Olson, E.N. Expression of mef2 genes in the mouse central nervous system suggests a role in neuronal maturation. J. Neurosci. 15, 5727–5738 (1995).

    Article  CAS  Google Scholar 

  10. Flavell, S.W. et al. Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 60, 1022–1038 (2008).

    Article  CAS  Google Scholar 

  11. Chowdhury, S. et al. Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52, 445–459 (2006).

    Article  CAS  Google Scholar 

  12. Shepherd, J.D. et al. Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors. Neuron 52, 475–484 (2006).

    Article  CAS  Google Scholar 

  13. Morrow, E.M. et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218–223 (2008).

    Article  CAS  Google Scholar 

  14. Greer, P.L. et al. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140, 704–716 (2010).

    Article  CAS  Google Scholar 

  15. Le Meur, N. et al. MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J. Med. Genet. 47, 22–29 (2010).

    Article  CAS  Google Scholar 

  16. McNaughton, B.L., Barnes, C.A., Meltzer, J. & Sutherland, R.J. Hippocampal granule cells are necessary for normal spatial learning but not for spatially-selective pyramidal cell discharge. Exp. Brain Res. 76, 485–496 (1989).

    Article  CAS  Google Scholar 

  17. LeDoux, J.E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).

    Article  CAS  Google Scholar 

  18. Davis, M. The role of the amygdala in fear and anxiety. Annu. Rev. Neurosci. 15, 353–375 (1992).

    Article  CAS  Google Scholar 

  19. Fanselow, M.S. & Gale, G.D. The amygdala, fear, and memory. Ann. NY Acad. Sci. 985, 125–134 (2003).

    Article  Google Scholar 

  20. Black, B.L. & Olson, E.N. Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu. Rev. Cell Dev. Biol. 14, 167–196 (1998).

    Article  CAS  Google Scholar 

  21. Pfeiffer, B.E. et al. Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. Neuron 66, 191–197 (2010).

    Article  CAS  Google Scholar 

  22. Chawla, M.K. et al. Sparse, environmentally selective expression of Arc RNA in the upper blade of the rodent fascia dentata by brief spatial experience. Hippocampus 15, 579–586 (2005).

    Article  CAS  Google Scholar 

  23. Frankland, P.W. et al. Consolidation of CS and US representations in associative fear conditioning. Hippocampus 14, 557–569 (2004).

    Article  Google Scholar 

  24. Wiltgen, B.J., Sanders, M.J., Anagnostaras, S.G., Sage, J.R. & Fanselow, M.S. Context fear learning in the absence of the hippocampus. J. Neurosci. 26, 5484–5491 (2006).

    Article  CAS  Google Scholar 

  25. Neely, M.D. et al. Localization of myocyte enhancer factor 2 in the rodent forebrain: regionally-specific cytoplasmic expression of MEF2A. Brain Res. 1274, 55–65 (2009).

    Article  CAS  Google Scholar 

  26. Sekeres, M.J., Neve, R.L., Frankland, P.W. & Josselyn, S.A. Dorsal hippocampal CREB is both necessary and sufficient for spatial memory. Learn. Mem. 17, 280–283 (2010).

    Article  CAS  Google Scholar 

  27. Josselyn, S.A. et al. Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala. J. Neurosci. 21, 2404–2412 (2001).

    Article  CAS  Google Scholar 

  28. McDonald, R.J. & White, N.M. A triple dissociation of memory systems: hippocampus, amygdala, and dorsal striatum. Behav. Neurosci. 107, 3–22 (1993).

    Article  CAS  Google Scholar 

  29. Moser, M.B., Trommald, M. & Andersen, P. An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses. Proc. Natl. Acad. Sci. USA 91, 12673–12675 (1994).

    Article  CAS  Google Scholar 

  30. O'Malley, A., O'Connell, C. & Regan, C.M. Ultrastructural analysis reveals avoidance conditioning to induce a transient increase in hippocampal dentate spine density in the 6 hour post-training period of consolidation. Neuroscience 87, 607–613 (1998).

    Article  CAS  Google Scholar 

  31. Buzsaki, G. The hippocampo-neocortical dialogue. Cereb. Cortex 6, 81–92 (1996).

    Article  CAS  Google Scholar 

  32. Wilson, M.A. & McNaughton, B.L. Reactivation of hippocampal ensemble memories during sleep. Science 265, 676–679 (1994).

    Article  CAS  Google Scholar 

  33. Shen, J., Kudrimoti, H.S., McNaughton, B.L. & Barnes, C.A. Reactivation of neuronal ensembles in hippocampal dentate gyrus during sleep after spatial experience. J. Sleep Res. 7 (suppl. 1), 6–16 (1998).

    Article  Google Scholar 

  34. Bunch, M.E. & Magdisck, W.K. The retention in rats of an incompletely learned maze solution for short intervals of time. J. Comp. Psychol. 16, 385–409 (1933).

    Article  Google Scholar 

  35. Shepherd, J.D. & Bear, M.F. New views of Arc, a master regulator of synaptic plasticity. Nat. Neurosci. 14, 279–284 (2011).

    Article  CAS  Google Scholar 

  36. Rial Verde, E.M., Lee-Osbourne, J., Worley, P.F., Malinow, R. & Cline, H.T. Increased expression of the immediate-early gene arc/arg3.1 reduces AMPA receptor-mediated synaptic transmission. Neuron 52, 461–474 (2006).

    Article  Google Scholar 

  37. Collingridge, G.L., Isaac, J.T. & Wang, Y.T. Receptor trafficking and synaptic plasticity. Nat. Rev. Neurosci. 5, 952–962 (2004).

    Article  CAS  Google Scholar 

  38. Malinow, R. & Malenka, R.C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).

    Article  CAS  Google Scholar 

  39. Gainey, M.A., Hurvitz-Wolff, J.R., Lambo, M.E. & Turrigiano, G.G. Synaptic scaling requires the GluR2 subunit of the AMPA receptor. J. Neurosci. 29, 6479–6489 (2009).

    Article  CAS  Google Scholar 

  40. Brebner, K. et al. Nucleus accumbens long-term depression and the expression of behavioral sensitization. Science 310, 1340–1343 (2005).

    Article  CAS  Google Scholar 

  41. Migues, P.V. et al. PKMzeta maintains memories by regulating GluR2-dependent AMPA receptor trafficking. Nat. Neurosci. 13, 630–634 (2010).

    Article  CAS  Google Scholar 

  42. Li, H. et al. Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc. Natl. Acad. Sci. USA 105, 9397–9402 (2008).

    Article  CAS  Google Scholar 

  43. Cajal, S.R. Sur les ganglions et plexus nerveux de l'intestin. C. R. Soc. Biol. (Paris) 45, 217–223 (1893).

    Google Scholar 

  44. Simon, D.J. et al. The microRNA miR-1 regulates a MEF-2-dependent retrograde signal at neuromuscular junctions. Cell 133, 903–915 (2008).

    Article  CAS  Google Scholar 

  45. Pickens, C.L., Golden, S.A., Adams-Deutsch, T., Nair, S.G. & Shaham, Y. Long-lasting incubation of conditioned fear in rats. Biol. Psychiatry 65, 881–886 (2009).

    Article  Google Scholar 

  46. Vetere, G. et al. Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory. Proc. Natl. Acad. Sci. USA 108, 8456–8460 (2011).

    Article  CAS  Google Scholar 

  47. Kandel, E.R. The biology of memory: a forty-year perspective. J. Neurosci. 29, 12748–12756 (2009).

    Article  CAS  Google Scholar 

  48. Ehlers, M.D. Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat. Neurosci. 6, 231–242 (2003).

    Article  CAS  Google Scholar 

  49. Fioravante, D. & Byrne, J.H. Protein degradation and memory formation. Brain Res. Bull. 85, 14–20 (2011).

    Article  CAS  Google Scholar 

  50. Yang, Q. et al. Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science 323, 124–127 (2009).

    Article  CAS  Google Scholar 

  51. Keppel, G. & Wickens, T.D. Design and Analysis: A Researcher's Handbook 4th edn. (Prentice Hall, 2004).

  52. Yiu, A.P., Rashid, A.J. & Josselyn, S.A. Increasing CREB function in the CA1 region of dorsal hippocampus rescues the spatial memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology 36, 2169–2186 (2011).

    Article  CAS  Google Scholar 

  53. Zalfa, F. et al. A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability. Nat. Neurosci. 10, 578–587 (2007).

    Article  CAS  Google Scholar 

  54. Karamboulas, C. et al. Disruption of MEF2 activity in cardiomyoblasts inhibits cardiomyogenesis. J. Cell Sci. 119, 4315–4321 (2006).

    Article  CAS  Google Scholar 

  55. Russo, S.J. et al. Nuclear factor kappa B signaling regulates neuronal morphology and cocaine reward. J. Neurosci. 29, 3529–3537 (2009).

    Article  CAS  Google Scholar 

  56. Clark, M.S. et al. Overexpression of 5-HT1B receptor in dorsal raphe nucleus using Herpes Simplex Virus gene transfer increases anxiety behavior after inescapable stress. J. Neurosci. 22, 4550–4562 (2002).

    Article  CAS  Google Scholar 

  57. Miller, R.R. & McDevitt, C.A. A quantitative microwell assay for chondrocyte cell adhesion. Anal. Biochem. 192, 380–383 (1991).

    Article  CAS  Google Scholar 

  58. Paxinos, G. & Franklin, K.B.J. The Mouse Brain in Stereotaxic Coordinates, 2nd edn. (Academic Press, San Diego, 2001).

  59. Teixeira, C.M., Pomedli, S.R., Maei, H.R., Kee, N. & Frankland, P.W. Involvement of the anterior cingulate cortex in the expression of remote spatial memory. J. Neurosci. 26, 7555–7564 (2006).

    Article  Google Scholar 

  60. Maei, H.R., Zaslavsky, K., Teixeira, C.M. & Frankland, P.W. What is the most sensitive measure of water maze probe test performance? Front. Integr. Neurosci. 3, 4 (2009).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank A. DeCristofaro, R. Braybon and M. Yamamoto for excellent technical assistance. This work was supported by grants from the Canadian Institutes of Health Research (CIHR; MOP-74650 (S.A.J.), MOP-86762 (P.W.F.)), EJLB Foundation (S.A.J.) and Natural Science and Engineering Research Council (S.A.J.). C.J.C., A.P.Y. and M.J.S. were supported by Restracomp Fellowships (Hospital for Sick Children), A.P.Y. received support from the Alzheimer's Society of Canada, M.J.S. received a CIHR Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award and a grant from the Faculty of Medicine at the University of Toronto, and C.J.C. received an Ontario Graduate Scholarship.

Author information

Author notes

  1. Jin-Hee Han

    Present address: Present address: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Yuseong-gu, Daejeon, Korea.,

  2. Christina J Cole and Valentina Mercaldo: These authors contributed equally to this work.

Authors and Affiliations

  1. Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada

    Christina J Cole, Valentina Mercaldo, Leonardo Restivo, Adelaide P Yiu, Melanie J Sekeres, Jin-Hee Han, Gisella Vetere, Tetyana Pekar, P Joel Ross, Paul W Frankland & Sheena A Josselyn

  2. Department of Physiology, University of Toronto, Toronto, Ontario, Canada

    Christina J Cole, Valentina Mercaldo, Leonardo Restivo, Adelaide P Yiu, Melanie J Sekeres, Jin-Hee Han, Gisella Vetere, Paul W Frankland & Sheena A Josselyn

  3. Institute of Medical Sciences (IMS), University of Toronto, Toronto, Ontario, Canada

    Valentina Mercaldo, Leonardo Restivo, Adelaide P Yiu, Jin-Hee Han, Gisella Vetere, Paul W Frankland & Sheena A Josselyn

  4. Cell Biology and Neurobiology Institute, National Research Council of Italy, S. Lucia Foundation, Rome, Italy

    Gisella Vetere

  5. Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Rachael L Neve

Authors
  1. Christina J Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valentina Mercaldo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leonardo Restivo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adelaide P Yiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Melanie J Sekeres
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin-Hee Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gisella Vetere
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tetyana Pekar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Joel Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rachael L Neve
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Paul W Frankland
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sheena A Josselyn
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.A.J. and P.W.F. designed, directed and coordinated the study. C.J.C., V.M., L.R. and T.P. conducted behavioral experiments . C.J.C., A.P.Y. and M.J.S. performed the surgeries. C.J.C., V.M. and L.R. performed spine analysis. V.M., L.R. and G.V. performed immunohistochemistry. V.M. and P.J.R. conducted the cell culture experiments. C.J.C., V.M. and L.R. performed statistical analysis. J.-H.H. designed several constructs. R.L.N. generated viral vectors, shRNA and commented extensively on the design of experiments and use of viral vectors. S.A.J. and P.W.F. wrote the manuscript, with assistance from C.J.C., V.M. and L.R.

Corresponding author

Correspondence to Sheena A Josselyn.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 (PDF 349 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cole, C., Mercaldo, V., Restivo, L. et al. MEF2 negatively regulates learning-induced structural plasticity and memory formation. Nat Neurosci 15, 1255–1264 (2012). https://doi.org/10.1038/nn.3189

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3189

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing