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

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.

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Figure 1: TrkB is phosphorylated at S478 at neuronal synapse.
Figure 2: S478 phosphorylation of TrkB is required for BDNF-induced spine morphogenesis and glutamate-induced spine enlargement.
Figure 3: S478 phosphorylation regulates the interaction between TrkB and the Rac GEF TIAM1.
Figure 4: Cdk5-mediated phosphorylation of TrkB at S478 is required for BDNF-induced Rac1 activity and glutamate-induced PAK phosphorylation.
Figure 5: Cdk5-mediated phosphorylation of TrkB at S478 is required for increased S6 phosphorylation and PSD-95 expression following NMDA receptor activation.
Figure 6: Impaired hippocampal LTP in TrkbS478A/S478A mutant mice.
Figure 7: TrkbS478A/S478A mice display impaired memory in Morris water maze and novel object recognition, but have normal fear memory.

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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.

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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.

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Correspondence to Nancy Y Ip.

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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

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