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.
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
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Huang, E.J. & Reichardt, L.F. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 72, 609–642 (2003).
Kandel, E.R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).
Lu, Y., Christian, K. & Lu, B. BDNF: A key regulator for protein synthesis–dependent LTP and long-term memory? Neurobiol. Learn. Mem. 89, 312–323 (2008).
Engert, F. & Bonhoeffer, T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399, 66–70 (1999).
Maletic-Savatic, M., Malinow, R. & Svoboda, K. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 283, 1923–1927 (1999).
Matsuzaki, M., Honkura, N. & Ellis-Davies, G.C.R. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766 (2004).
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).
Tanaka, J. et al. Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319, 1683–1687 (2008).
Chen, Z.Y. et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314, 140–143 (2006).
An, J.J. et al. Distinct role of long 3' UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134, 175–187 (2008).
Ninan, I. et al. The BDNF Val66Met polymorphism impairs NMDA receptor–dependent synaptic plasticity in the hippocampus. J. Neurosci. 30, 8866–8870 (2010).
Tyler, W.J. & Pozzo-Miller, L.D. 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).
Ji, Y., Pang, P.T., Feng, L. & Lu, B. Cyclic AMP controls BDNF-induced TrkB phosphorylation and dendritic spine formation in mature hippocampal neurons. Nat. Neurosci. 8, 164–172 (2005).
Rex, C.S. et al. Brain-derived neurotrophic factor promotes long-term potentiation–related cytoskeletal changes in adult hippocampus. J. Neurosci. 27, 3017–3029 (2007).
Minichiello, L. et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24, 401–414 (1999).
Minichiello, L. et al. Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 36, 121–137 (2002).
Cheung, Z.H., Chin, W.H., Chen, Y., Ng, Y.P. & Ip, N.Y. Cdk5 is involved in BDNF-stimulated dendritic growth in hippocampal neurons. PLoS Biol. 5, e63 (2007).
Lai, K.O. & Ip, N.Y. Recent advances in understanding the roles of Cdk5 in synaptic plasticity. Biochim. Biophys. Acta 1792, 741–745 (2009).
Matsuzaki, M. et al. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat. Neurosci. 4, 1086–1092 (2001).
Harvey, C.D. & Svoboda, K. Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature 450, 1195–1200 (2007).
Korkotian, E. & Segal, M. Morphological constraints on calcium-dependent glutamate receptor trafficking into individual dendritic spine. Cell Calcium 42, 41–57 (2007).
Nakayama, A.Y. & Luo, L.Q. Intracellular signaling pathways that regulate dendritic spine morphogenesis. Hippocampus 10, 582–586 (2000).
Tashiro, A., Minden, A. & Yuste, R. Regulation of dendritic spine morphology by the Rho family of small GTPases: antagonistic roles of Rac and Rho. Cereb. Cortex 10, 927–938 (2000).
Miyamoto, Y., Yamauchi, J., Tanoue, A., Wu, C. & Mobley, W.C. 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).
Tolias, K.F. 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).
Xie, Z. et al. Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. Neuron 56, 640–656 (2007).
Saneyoshi, T. et al. Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/beta PIX signaling complex. Neuron 57, 94–107 (2008).
Barco, A. 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).
Buchsbaum, R.J., Connolly, B.A. & Feig, L.A. 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).
Lu, W. 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).
Richter, J.D. & Klann, E. Making synaptic plasticity and memory last: mechanisms of translational regulation. Genes Dev. 23, 1–11 (2009).
Todd, P.K., Mack, K.J. & Malter, J.S. 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).
Figurov, A., Pozzo-Miller, L.D., Olafsson, P., Wang, T. & Lu, B. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381, 706–709 (1996).
Ohshima, T. et al. Impairment of hippocampal long-term depression and defective spatial learning and memory in p35 mice. J. Neurochem. 94, 917–925 (2005).
Kang, H., Welcher, A.A., Shelton, D. & Schuman, E.M. Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron 19, 653–664 (1997).
Patterson, S.L. 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).
Abel, T. 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).
Miller, S. et al. Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation. Neuron 36, 507–519 (2002).
Kelleher, R.J. III, Govindarajan, A., Jung, H.Y., Kang, H. & Tonegawa, S. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467–479 (2004).
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).
Rampon, C. et al. Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice. Nat. Neurosci. 3, 238–244 (2000).
Wei, F.Y. et al. Control of cyclin-dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability. J. Neurochem. 93, 502–512 (2005).
Fischer, A., Sananbenesi, F., Pang, P.T., Lu, B. & Tsai, L.H. Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48, 825–838 (2005).
Hawasli, A.H. et al. Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat. Neurosci. 10, 880–886 (2007).
Li, B.S. et al. Regulation of NMDA receptors by cyclin-dependent kinase-5. Proc. Natl. Acad. Sci. USA 98, 12742–12747 (2001).
Morabito, M.A., Sheng, M. & Tsai, L.H. Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons. J. Neurosci. 24, 865–876 (2004).
Bramham, C.R. Local protein synthesis, actin dynamics and LTP consolidation. Curr. Opin. Neurobiol. 18, 524–531 (2008).
Bolton, M.M., Pittman, A.J. & Lo, D.C. Brain-derived neurotrophic factor differentially regulates excitatory and inhibitory synaptic transmission in hippocampal cultures. J. Neurosci. 20, 3221–3232 (2000).
van der Geer, P., Hunter, T. & Lindberg, R.A. Receptor protein-tyrosine kinases and their signal transduction pathways. Annu. Rev. Cell Biol. 10, 251–337 (1994).
Fu, A.K. et al. Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction. Nat. Neurosci. 4, 374–381 (2001).
Liu, P. et al. Bcl11a is essential for normal lymphoid development. Nat. Immunol. 4, 525–532 (2003).
Southon, E. & Tessarollo, L. Manipulating mouse embryonic stem cells. Methods Mol. Biol. 530, 165–185 (2009).
Reid, S.W. & Tessarollo, L. Isolation, microinjection and transfer of mouse blastocysts. Methods Mol. Biol. 530, 269–285 (2009).
Xie, H. 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).
Fu, W.Y. et al. Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat. Neurosci. 10, 67–76 (2007).
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
Authors and Affiliations
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–11 (PDF 1269 kb)
Rights and permissions
About this article
Cite this article
Lai, KO., Wong, A., Cheung, MC. et al. TrkB phosphorylation by Cdk5 is required for activity-dependent structural plasticity and spatial memory. Nat Neurosci 15, 1506–1515 (2012). https://doi.org/10.1038/nn.3237
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn.3237
This article is cited by
-
Three decades of Cdk5
Journal of Biomedical Science (2021)
-
Astrocytic microdomains from mouse cortex gain molecular control over long-term information storage and memory retention
Communications Biology (2021)
-
RPS23RG1 modulates tau phosphorylation and axon outgrowth through regulating p35 proteasomal degradation
Cell Death & Differentiation (2021)
-
Spine impairment in mice high-expressing neuregulin 1 due to LIMK1 activation
Cell Death & Disease (2021)
-
p39-associated Cdk5 activity regulates dendritic morphogenesis
Scientific Reports (2020)