Article | Published:

TrkB phosphorylation by Cdk5 is required for activity-dependent structural plasticity and spatial memory

Nature Neuroscience 15, 1506–1515 (2012) | Download Citation

Subjects

Abstract

The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB participate in diverse neuronal functions, including activity-dependent synaptic plasticity that is crucial for learning and memory. On binding to BDNF, TrkB is not only autophosphorylated at tyrosine residues but also undergoes serine phosphorylation at S478 by the serine/threonine kinase cyclin-dependent kinase 5 (Cdk5). However, the in vivo function of this serine phosphorylation remains unknown. We generated knock-in mice lacking this serine phosphorylation (TrkbS478A/S478A mice) and found that the TrkB phosphorylation–deficient mice displayed impaired spatial memory and compromised hippocampal long-term potentiation (LTP). S478 phosphorylation of TrkB regulates its interaction with the Rac1-specific guanine nucleotide exchange factor TIAM1, leading to activation of Rac1 and phosphorylation of S6 ribosomal protein during activity-dependent dendritic spine remodeling. These findings reveal the importance of Cdk5-mediated S478 phosphorylation of TrkB in activity-dependent structural plasticity, which is crucial for LTP and spatial memory formation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

References

  1. 1.

    & Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 72, 609–642 (2003).

  2. 2.

    The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).

  3. 3.

    , & BDNF: A key regulator for protein synthesis–dependent LTP and long-term memory? Neurobiol. Learn. Mem. 89, 312–323 (2008).

  4. 4.

    & Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399, 66–70 (1999).

  5. 5.

    , & Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 283, 1923–1927 (1999).

  6. 6.

    , & & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766 (2004).

  7. 7.

    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).

  8. 8.

    et al. Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319, 1683–1687 (2008).

  9. 9.

    et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314, 140–143 (2006).

  10. 10.

    et al. Distinct role of long 3' UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134, 175–187 (2008).

  11. 11.

    et al. The BDNF Val66Met polymorphism impairs NMDA receptor–dependent synaptic plasticity in the hippocampus. J. Neurosci. 30, 8866–8870 (2010).

  12. 12.

    & BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J. Neurosci. 21, 4249–4258 (2001).

  13. 13.

    , , & Cyclic AMP controls BDNF-induced TrkB phosphorylation and dendritic spine formation in mature hippocampal neurons. Nat. Neurosci. 8, 164–172 (2005).

  14. 14.

    et al. Brain-derived neurotrophic factor promotes long-term potentiation–related cytoskeletal changes in adult hippocampus. J. Neurosci. 27, 3017–3029 (2007).

  15. 15.

    et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24, 401–414 (1999).

  16. 16.

    et al. Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 36, 121–137 (2002).

  17. 17.

    , , , & Cdk5 is involved in BDNF-stimulated dendritic growth in hippocampal neurons. PLoS Biol. 5, e63 (2007).

  18. 18.

    & Recent advances in understanding the roles of Cdk5 in synaptic plasticity. Biochim. Biophys. Acta 1792, 741–745 (2009).

  19. 19.

    et al. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat. Neurosci. 4, 1086–1092 (2001).

  20. 20.

    & Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature 450, 1195–1200 (2007).

  21. 21.

    & Morphological constraints on calcium-dependent glutamate receptor trafficking into individual dendritic spine. Cell Calcium 42, 41–57 (2007).

  22. 22.

    & Intracellular signaling pathways that regulate dendritic spine morphogenesis. Hippocampus 10, 582–586 (2000).

  23. 23.

    , & Regulation of dendritic spine morphology by the Rho family of small GTPases: antagonistic roles of Rac and Rho. Cereb. Cortex 10, 927–938 (2000).

  24. 24.

    , , , & TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology. Proc. Natl. Acad. Sci. USA 103, 10444–10449 (2006).

  25. 25.

    et al. The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines. Neuron 45, 525–538 (2005).

  26. 26.

    et al. Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. Neuron 56, 640–656 (2007).

  27. 27.

    et al. Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/beta PIX signaling complex. Neuron 57, 94–107 (2008).

  28. 28.

    et al. Gene expression profiling of facilitated L-LTP in VP16-CREB mice reveals that BDNF is critical for the maintenance of LTP and its synaptic capture. Neuron 48, 123–137 (2005).

  29. 29.

    , & Regulation of p70 S6 kinase by complex formation between the rac guanine nucleotide exchange factor (Rac-GEF) Tiam1 and the scaffold spinophilin. J. Biol. Chem. 278, 18833–18841 (2003).

  30. 30.

    et al. Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29, 243–254 (2001).

  31. 31.

    & Making synaptic plasticity and memory last: mechanisms of translational regulation. Genes Dev. 23, 1–11 (2009).

  32. 32.

    , & The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95. Proc. Natl. Acad. Sci. USA 100, 14374–14378 (2003).

  33. 33.

    , , , & Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381, 706–709 (1996).

  34. 34.

    et al. Impairment of hippocampal long-term depression and defective spatial learning and memory in p35 mice. J. Neurochem. 94, 917–925 (2005).

  35. 35.

    , , & Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron 19, 653–664 (1997).

  36. 36.

    et al. Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron 32, 123–140 (2001).

  37. 37.

    et al. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 88, 615–626 (1997).

  38. 38.

    et al. Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation. Neuron 36, 507–519 (2002).

  39. 39.

    , , , & Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467–479 (2004).

  40. 40.

    , , & Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol. Psychiatry 12, 656–670 (2007).

  41. 41.

    et al. Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice. Nat. Neurosci. 3, 238–244 (2000).

  42. 42.

    et al. Control of cyclin-dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability. J. Neurochem. 93, 502–512 (2005).

  43. 43.

    , , , & Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48, 825–838 (2005).

  44. 44.

    et al. Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat. Neurosci. 10, 880–886 (2007).

  45. 45.

    et al. Regulation of NMDA receptors by cyclin-dependent kinase-5. Proc. Natl. Acad. Sci. USA 98, 12742–12747 (2001).

  46. 46.

    , & Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons. J. Neurosci. 24, 865–876 (2004).

  47. 47.

    Local protein synthesis, actin dynamics and LTP consolidation. Curr. Opin. Neurobiol. 18, 524–531 (2008).

  48. 48.

    , & Brain-derived neurotrophic factor differentially regulates excitatory and inhibitory synaptic transmission in hippocampal cultures. J. Neurosci. 20, 3221–3232 (2000).

  49. 49.

    , & Receptor protein-tyrosine kinases and their signal transduction pathways. Annu. Rev. Cell Biol. 10, 251–337 (1994).

  50. 50.

    et al. Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction. Nat. Neurosci. 4, 374–381 (2001).

  51. 51.

    et al. Bcl11a is essential for normal lymphoid development. Nat. Immunol. 4, 525–532 (2003).

  52. 52.

    & Manipulating mouse embryonic stem cells. Methods Mol. Biol. 530, 165–185 (2009).

  53. 53.

    & Isolation, microinjection and transfer of mouse blastocysts. Methods Mol. Biol. 530, 269–285 (2009).

  54. 54.

    et al. Brain-derived neurotrophic factor rescues and prevents chronic intermittent hypoxia-induced impairment of hippocampal long-term synaptic plasticity. Neurobiol. Dis. 40, 155–162 (2010).

  55. 55.

    et al. Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat. Neurosci. 10, 67–76 (2007).

Download references

Acknowledgements

We are grateful to A. Kulkarni (National Institutes of Health) and T. Curran (University of Pennsylvania) for the Cdk5−/− mice, L.-H. Tsai (Massachusetts Institute of Technology) for the p35−/− mice, M. Greenberg (Harvard Medical School) for the phospho-TIAM1 and phospho-PAK antibodies, W. Mobley (University of California, San Diego) for TIAM1 expression constructs, and L. Reichardt (University of California, San Francisco) for the chicken antibody to TrkB. We thank C. Kwong, B. Lai, P. Sun, B. Butt, Y. Liang, H. Chuang, Y. Dai and K. Ho for their excellent technical assistance, Amy Fu and Ada Fu for critical reading of the manuscript, and members of the Ip laboratory for many helpful discussions. This study was supported in part by the Research Grants Council of Hong Kong (HKUST 661109, 661309, 660810, 661010 and 661111), the Area of Excellence Scheme of the University Grants Committee (AoE/B-15/01) and the S.H. Ho Foundation. N.Y.I. was the recipient of Croucher Foundation Senior Research Fellowship, and K.-O.L. and Z.H.C. were the recipients of Croucher Foundation Research Fellowship. M.E.P. and L.T. were supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, US National Institutes of Health.

Author information

Affiliations

  1. Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China.

    • Kwok-On Lai
    • , Alan S L Wong
    • , Man-Chun Cheung
    • , Pei Xu
    • , Zhuoyi Liang
    • , Ka-Chun Lok
    • , Zelda H Cheung
    •  & Nancy Y Ip

  2. Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.

    • Kwok-On Lai
    • , Alan S L Wong
    • , Man-Chun Cheung
    • , Pei Xu
    • , Zhuoyi Liang
    • , Ka-Chun Lok
    • , Zelda H Cheung
    •  & Nancy Y Ip

  3. State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.

    • Kwok-On Lai
    • , Alan S L Wong
    • , Man-Chun Cheung
    • , Pei Xu
    • , Zhuoyi Liang
    • , Ka-Chun Lok
    • , Zelda H Cheung
    •  & Nancy Y Ip

  4. School of Biomedical Science, The Chinese University of Hong Kong, Hong Kong, China.

    • Hui Xie
    •  & Wing-Ho Yung

  5. Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.

    • Mary E Palko
    •  & Lino Tessarollo

Authors

  1. Search for Kwok-On Lai in:

  2. Search for Alan S L Wong in:

  3. Search for Man-Chun Cheung in:

  4. Search for Pei Xu in:

  5. Search for Zhuoyi Liang in:

  6. Search for Ka-Chun Lok in:

  7. Search for Hui Xie in:

  8. Search for Mary E Palko in:

  9. Search for Wing-Ho Yung in:

  10. Search for Lino Tessarollo in:

  11. Search for Zelda H Cheung in:

  12. Search for Nancy Y Ip in:

Contributions

K.-O.L. and N.Y.I. supervised the project. K.-O.L., A.S.L.W., Z.H.C. and N.Y.I. designed the experiments. K.-O.L., A.S.L.W., M.-C.C., P.X., Z.L. and K.-C.L. conducted the experiments. K.-O.L., A.S.L.W., M.-C.C., P.X., Z.L., K.-C.L. and N.Y.I. carried out the data analyses. W.-H.Y. designed and carried out the data analyses of the electrophysiology experiments and H.X. performed the electrophysiology experiments and data analysis. L.T. and M.E.P designed and generated the knock-in mice. K.-O.L., Z.H.C. and N.Y.I. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nancy Y Ip.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–11

To obtain permission to re-use content from this article visit RightsLink.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nn.3237