Abstract
Learning is accompanied by modulation of postsynaptic signal transduction pathways in neurons. Although the neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) has been implicated in cognitive disorders, its role in learning has been obscured by the perinatal lethality of constitutive knockout mice. Here we report that conditional knockout of Cdk5 in the adult mouse brain improved performance in spatial learning tasks and enhanced hippocampal long-term potentiation and NMDA receptor (NMDAR)-mediated excitatory postsynaptic currents. Enhanced synaptic plasticity in Cdk5 knockout mice was attributed to reduced NR2B degradation, which caused elevations in total, surface and synaptic NR2B subunit levels and current through NR2B-containing NMDARs. Cdk5 facilitated the degradation of NR2B by directly interacting with both it and its protease, calpain. These findings reveal a previously unknown mechanism by which Cdk5 facilitates calpain-mediated proteolysis of NR2B and may control synaptic plasticity and learning.
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Acknowledgements
We thank B. Potts, S. Gold, J. Pick and M. Waung for assistance with experiments, D. Metzger for characterization of Cre-ERT line, C. Steffen for assistance with animal husbandry and K. Bayer for the NR2B clone. We thank A. Nairn and E. Nestler for comments and discussion and are grateful to the Medical Scientist Training Program at the University of Texas Southwestern Medical Center. This work was made possible by the US National Institutes on Drug Abuse National Research Service Award training grant (A.H.H.), US National Institutes of Health individual National Research Service Awards (D.R.B., C.N.), US National Alliance for Research on Schizophrenia and Depression Young Investigator awards (C.M.P. and D.C.C.), grant funding from the US National Institutes on Drug Abuse (P.G., D.C.C. and J.A.B.) and Mental Health (P.G., C.M.P. and J.A.B.) and the Ella McFadden Charitable Trust Fund at the Southwestern Medical Foundation (J.A.B).
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A.H.H. performed knockout optimization, histology, learning behavior testing, extracellular recordings, slice pharmacology, biochemistry and data analysis. D.R.B. established the mouse colony, optimized genotyping and histology and performed anxiety behavior testing. C.N. performed whole-cell voltage-clamp recordings. J.W.K. assisted in genotyping and histology. K.H. prepared synaptosomes and recombinant Cdk5. P.C. and P.G. provided mouse lines. C.M.P., D.C.C. and J.A.B. designed and supervised the experiments conducted in their laboratories. A.H.H. and J.A.B. prepared the manuscript. All authors contributed to experimental design, discussed the results and commented on the report.
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Supplementary information
Supplementary Fig. 1
Controls for hippocampal Cdk5 levels, cytoarchitecture and detailed characterization of Cdk5 knockout. (PDF 5225 kb)
Supplementary Fig. 2
Controls for preknockout memory and effects of Cdk5 knockout on nociception, anxiety and swim velocity. (PDF 1320 kb)
Supplementary Fig. 3
Increased whole-cell EPSC NMDA:AMPA charge ratio in Cdk5 knockout slices using an alternative measurement in CA1 pyramidal cells. (PDF 481 kb)
Supplementary Fig. 4
Analyses of synaptic NR2B level, mRNA expression and C-terminus NR2B phosphorylation. (PDF 2460 kb)
Supplementary Fig. 5
Coimmunoprecipitation analysis in Cdk5 knockout hippocampus. (PDF 1087 kb)
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Hawasli, A., Benavides, D., Nguyen, C. et al. Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat Neurosci 10, 880–886 (2007). https://doi.org/10.1038/nn1914
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DOI: https://doi.org/10.1038/nn1914
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