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

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 (Trkb(S478A/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.

Pubmed ID: 23064382


  • Lai KO
  • Wong AS
  • Cheung MC
  • Xu P
  • Liang Z
  • Lok KC
  • Xie H
  • Palko ME
  • Yung WH
  • Tessarollo L
  • Cheung ZH
  • Ip NY


Nature neuroscience

Publication Data

November 29, 2012

Associated Grants

  • Agency: Intramural NIH HHS, Id:

Mesh Terms

  • Analysis of Variance
  • Animals
  • Brain
  • Brain-Derived Neurotrophic Factor
  • Cells, Cultured
  • Cyclin-Dependent Kinase 5
  • Dendritic Spines
  • Excitatory Amino Acid Antagonists
  • Excitatory Postsynaptic Potentials
  • Glutamic Acid
  • Green Fluorescent Proteins
  • Guanine Nucleotide Exchange Factors
  • Guanylate Kinase
  • Humans
  • Immunoprecipitation
  • In Vitro Techniques
  • Long-Term Potentiation
  • Maze Learning
  • Membrane Proteins
  • Memory
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Nerve Tissue Proteins
  • Neurons
  • Phosphorylation
  • Quinoxalines
  • Rats
  • Receptor, trkB
  • Ribosomal Protein S6 Kinases
  • Serine
  • Silver Staining
  • Spatial Behavior
  • Synaptophysin
  • Time Factors
  • Transfection
  • rac1 GTP-Binding Protein