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.

β-catenin is required for memory consolidation

Nature Neuroscience volume 11, pages 1319–1326 (2008)Cite this article

Abstract

β-catenin has been implicated in neuronal synapse regulation and remodeling. Here we have examined β-catenin expression in the adult mouse brain and its role in amygdala-dependent learning and memory. We found alterations in β-catenin mRNA and protein phosphorylation during fear-memory consolidation. Such alterations correlated with a change in the association of β-catenin with cadherin. Pharmacologically, this consolidation was enhanced by lithium-mediated facilitation of β-catenin. Genetically, the role of β-catenin was confirmed with site-specific deletions of loxP-flanked Ctnnb1 (encoding β-catenin) in the amygdala. Baseline locomotion, anxiety-related behaviors and acquisition or expression of conditioned fear were normal. However, amygdala-specific deletion of Ctnnb1 prevented the normal transfer of newly formed fear learning into long-term memory. Thus, β-catenin may be required in the amygdala for the normal consolidation, but not acquisition, of fear memory. This suggests a general role for β-catenin in the synaptic remodeling and stabilization underlying long-term memory in adults.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: β-catenin expression in the adult mouse brain.
Figure 2: β-catenin gene expression in the amygdala is increased after fear conditioning.
Figure 3: Phosphorylation states of β-catenin and GSK-3β are altered after fear conditioning.
Figure 4: LiCl decreases GSK-3β-mediated β-catenin phosphorylation in the amygdala and enhances learning.
Figure 5: Region-specific deletion of β-catenin in the adult brain.
Figure 6: Amygdala-specific β-catenin deletions do not affect baseline anxiety or activity measures.
Figure 7: Amygdala-specific Ctnnb1 deletion prevents the consolidation, but not expression, of conditioned fear.

References

  1. Harris, K.M. & Kater, S.B. Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu. Rev. Neurosci. 17, 341–371 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nagerl, U.V., Eberhorn, N., Cambridge, S.B. & Bonhoeffer, T. Bidirectional activity-dependent morphological plasticity in hippocampal neurons. Neuron 44, 759–767 (2004).

    Article  PubMed  Google Scholar 

  5. Yuste, R. & Bonhoeffer, T. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu. Rev. Neurosci. 24, 1071–1089 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Gumbiner, B.M. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell 84, 345–357 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Murase, S., Mosser, E. & Schuman, E.M. Depolarization drives beta-catenin into neuronal spines promoting changes in synaptic structure and function. Neuron 35, 91–105 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Salinas, P.C. & Price, S.R. Cadherins and catenins in synapse development. Curr. Opin. Neurobiol. 15, 73–80 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Takeichi, M. & Abe, K. Synaptic contact dynamics controlled by cadherin and catenins. Trends Cell Biol. 15, 216–221 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Logan, C.Y. & Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 20, 781–810 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Moon, R.T., Kohn, A.D., De Ferrari, G.V. & Kaykas, A. WNT and beta-catenin signalling: diseases and therapies. Nat. Rev. Genet. 5, 691–701 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Chen, J., Park, C.S. & Tang, S.J. Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation. J. Biol. Chem. 281, 11910–11916 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Machon, O., van den Bout, C.J., Backman, M., Kemler, R. & Krauss, S. Role of beta-catenin in the developing cortical and hippocampal neuroepithelium. Neuroscience 122, 129–143 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Roura, S., Miravet, S., Piedra, J., Garcia de Herreros, A. & Dunach, M. Regulation of E-cadherin/Catenin association by tyrosine phosphorylation. J. Biol. Chem. 274, 36734–36740 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Behrens, J. et al. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science 280, 596–599 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Peifer, M., Pai, L.M. & Casey, M. Phosphorylation of the Drosophila adherens junction protein Armadillo: roles for wingless signal and zeste-white 3 kinase. Dev. Biol. 166, 543–556 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Yost, C. et al. The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 10, 1443–1454 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Gould, T.D., O'Donnell, K.C., Picchini, A.M. & Manji, H.K. Strain differences in lithium attenuation of D-amphetamine-induced hyperlocomotion: a mouse model for the genetics of clinical response to lithium. Neuropsychopharmacology 32, 1321–1333 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Davies, S.P., Reddy, H., Caivano, M. & Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351, 95–105 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Brault, V. et al. Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. Development 128, 1253–1264 (2001).

    CAS  PubMed  Google Scholar 

  21. Piedra, J. et al. Regulation of beta-catenin structure and activity by tyrosine phosphorylation. J. Biol. Chem. 276, 20436–20443 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Bamji, S.X., Rico, B., Kimes, N. & Reichardt, L.F. BDNF mobilizes synaptic vesicles and enhances synapse formation by disrupting cadherin-beta-catenin interactions. J. Cell Biol. 174, 289–299 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rattiner, L.M., Davis, M., French, C.T. & Ressler, K.J. Brain-derived neurotrophic factor and tyrosine kinase receptor B involvement in amygdala-dependent fear conditioning. J. Neurosci. 24, 4796–4806 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gould, T.D. et al. Beta-catenin overexpression in the mouse brain phenocopies lithium-sensitive behaviors. Neuropsychopharmacology 32, 2173–2183 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. McGaugh, J.L. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu. Rev. Neurosci. 27, 1–28 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. McGaugh J.L., Roozendaal, B. Role of adrenal stress hormones in forming lasting memories in the brain. Curr. Opin. Neurobiol. 12, 205–210 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Chhatwal, J.P., Hammack, S.E., Jasnow, A.M., Rainnie, D.G. & Ressler, K.J. Identification of cell-type-specific promoters within the brain using lentiviral vectors. Gene Ther. 14, 575–583 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chhatwal, J.P., Stanek-Rattiner, L., Davis, M. & Ressler, K.J. Amygdala BDNF signaling is required for consolidation but not encoding of extinction. Nat. Neurosci. 9, 870–872 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Heldt, S.A., Stanek, L., Chhatwal, J.P. & Ressler, K.J. Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol. Psychiatry 12, 656–670 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Naldini, L., Blomer, U., Gage, F.H., Trono, D. & Verma, I.M. Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc. Natl. Acad. Sci. USA 93, 11382–11388 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Naldini, L. et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Tiscornia, G., Singer, O. & Verma, I.M. Production and purification of lentiviral vectors. Nat. Protoc. 1, 241–245 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Zufferey, R., Donello, J.E., Trono, D. & Hope, T.J. Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by retroviral vectors. J. Virol. 73, 2886–2892 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Heldt, S.A., Stanek, L., Chhatwal, J.P. & Ressler, K.J. Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol. Psychiatry 12, 656–670 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jones, S.V., Heldt, S.A., Davis, M. & Ressler, K.J. Olfactory-mediated fear conditioning in mice: simultaneous measurements of fear-potentiated startle and freezing. Behav. Neurosci. 119, 329–335 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Paxinos, G. & Watston, C. The Mouse Brain in Stereotaxic Coordinates (Academic, New York, 2003).

    Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health (MH069884, DA019624 and AG025688), the National Science Foundation (GRFP DGE-0234618), the Center for Behavioral Neuroscience (NSF agreement IBN-987675), the Burroughs Wellcome Fund and an NIH/National Center for Research Resources base grant (P51RR000165) to the Yerkes National Primate Research Center.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Howard Hughes Medical Institute, Yerkes National Primate Research Center, Emory University, 954 Gatewood Drive, Atlanta, 30329, Georgia, USA

    Kimberly A Maguschak & Kerry J Ressler

Authors
  1. Kimberly A Maguschak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kerry J Ressler
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.A.M. initiated the project, conducted the experiments and data analysis and wrote the draft versions of the manuscript. K.J.R. supervised the project, assisted with data analysis and experimental planning, and contributed to draft and revised versions of the manuscript.

Corresponding author

Correspondence to Kerry J Ressler.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 and Supplementary Methods (PDF 235 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Maguschak, K., Ressler, K. β-catenin is required for memory consolidation. Nat Neurosci 11, 1319–1326 (2008). https://doi.org/10.1038/nn.2198

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2198

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