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Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation

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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Figure 1: Conditional loss of Cdk5 in adult mouse hippocampus.
Figure 2: Superior performance of conditional Cdk5 KO mice in contextual fear conditioning, extinction and water-maze reversal learning and memory tasks.
Figure 3: Enhanced synaptic plasticity and NMDAR-mediated currents in the hippocampal SC-CA1 pathway of conditional Cdk5 KO mice.
Figure 4: Increased ifenprodil-sensitive NMDAR-mediated current and NR2B levels as a result of reduced calpain activity account for enhanced synaptic plasticity in Cdk5 KO mice.

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References

  1. Sweatt, J.D. Mechanisms of Memory (Elsevier, San Diego, California, 2003).

    Google Scholar 

  2. Whitlock, J.R., Heynen, A.J., Shuler, M.G. & Bear, M.F. Learning induces long-term potentiation in the hippocampus. Science 313, 1093–1097 (2006).

    Article  CAS  Google Scholar 

  3. Bibb, J.A. et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410, 376–380 (2001).

    Article  CAS  Google Scholar 

  4. Bibb, J.A. et al. Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402, 669–671 (1999).

    Article  CAS  Google Scholar 

  5. Cheung, Z.H., Fu, A.K.Y. & Ip, N.Y. Synaptic roles of Cdk5: implications in higher cognitive functions and neurodegenerative diseases. Neuron 50, 13–18 (2006).

    Article  CAS  Google Scholar 

  6. 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).

    Article  CAS  Google Scholar 

  7. Fischer, A., Sananbenesi, F., Schrick, C., Spiess, J. & Radulovic, J. Cyclin-dependent kinase 5 is required for associative learning. J. Neurosci. 22, 3700–3707 (2002).

    Article  CAS  Google Scholar 

  8. Gilmore, E.C., Ohshima, T., Goffinet, A.M., Kulkarni, A.B. & Herrup, K. Cyclin-dependent kinase 5–deficient mice demonstrate novel developmental arrest in cerebral cortex. J. Neurosci. 18, 6370–6377 (1998).

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. Ohshima, T. et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc. Natl. Acad. Sci. USA 93, 11173–11178 (1996).

    Article  CAS  Google Scholar 

  11. Patrick, G.N. et al. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615–622 (1999).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. Yan, Z., Chi, P., Bibb, J.A., Ryan, T.A. & Greengard, P. Roscovitine: a novel regulator of P/Q-type calcium channels and transmitter release in central neurons. J. Physiol. (Lond.) 540, 761–770 (2002).

    Article  CAS  Google Scholar 

  14. Weber, P., Metzger, D. & Chambon, P. Temporally controlled targeted somatic mutagenesis in the mouse brain. Eur. J. Neurosci. 14, 1777–1783 (2001).

    Article  CAS  Google Scholar 

  15. Tang, Y.P. et al. Genetic enhancement of learning and memory in mice. Nature 401, 63–69 (1999).

    Article  CAS  Google Scholar 

  16. Tsien, J.Z., Huerta, P.T. & Tonegawa, S. The essential role of hippocampal CA1 NMDA receptor–dependent synaptic plasticity in spatial memory. Cell 87, 1327–1338 (1996).

    Article  CAS  Google Scholar 

  17. Bernasconi-Guastalla, S., Wolfer, D.P. & Lipp, H.P. Hippocampal mossy fibers and swimming navigation in mice: correlations with size and left-right asymmetries. Hippocampus 4, 53–63 (1994).

    Article  CAS  Google Scholar 

  18. Nakazawa, K. et al. Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron 38, 305–315 (2003).

    Article  CAS  Google Scholar 

  19. Angelo, M., Plattner, F., Irvine, E.E. & Giese, K.P. Improved reversal learning and altered fear conditioning in transgenic mice with regionally restricted p25 expression. Eur. J. Neurosci. 18, 423–431 (2003).

    Article  Google Scholar 

  20. Monyer, H., Burnashev, N., Laurie, D.J., Sakmann, B. & Seeburg, P.H. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529–540 (1994).

    Article  CAS  Google Scholar 

  21. Chenard, B.L. & Menniti, F.S. Antagonists selective for NMDA receptors containing the NR2B subunit. Curr. Pharm. Des. 5, 381–404 (1999).

    CAS  PubMed  Google Scholar 

  22. Picconi, B. et al. NR2B subunit exerts a critical role in postischemic synaptic plasticity. Stroke 37, 1895–1901 (2006).

    Article  Google Scholar 

  23. Liu, L. et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304, 1021–1024 (2004).

    Article  CAS  Google Scholar 

  24. Guttmann, R.P. et al. Specific proteolysis of the NR2 subunit at multiple sites by calpain. J. Neurochem. 78, 1083–1093 (2001).

    Article  CAS  Google Scholar 

  25. Guttmann, R.P. et al. Proteolysis of the N-methyl-D-aspartate receptor by calpain in situ. J. Pharmacol. Exp. Ther. 302, 1023–1030 (2002).

    Article  CAS  Google Scholar 

  26. Simpkins, K.L. et al. Selective activation induced cleavage of the NR2B subunit by calpain. J. Neurosci. 23, 11322–11331 (2003).

    Article  CAS  Google Scholar 

  27. Zhao, M.G. et al. Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory. Neuron 47, 859–872 (2005).

    Article  CAS  Google Scholar 

  28. Kutsuwada, T. et al. Impairment of suckling response, trigeminal neuronal pattern formation and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice. Neuron 16, 333–344 (1996).

    Article  CAS  Google Scholar 

  29. Chung, H.J., Huang, Y.H., Lau, L.F. & Huganir, R.L. Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand. J. Neurosci. 24, 10248–10259 (2004).

    Article  CAS  Google Scholar 

  30. Husi, H., Ward, M.A., Choudhary, J.S., Blackstock, W.P. & Grant, S.G. Proteomic analysis of NMDA receptor–adhesion protein signaling complexes. Nat. Neurosci. 3, 661–669 (2000).

    Article  CAS  Google Scholar 

  31. Lee, M.S. et al. Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405, 360–364 (2000).

    Article  CAS  Google Scholar 

  32. Liu, M.C. et al. Comparing calpain- and caspase-3–mediated degradation patterns in traumatic brain injury by differential proteome analysis. Biochem. J. 394, 715–725 (2006).

    Article  CAS  Google Scholar 

  33. Dong, Y.N., Waxman, E.A. & Lynch, D.R. Interactions of postsynaptic density-95 and the NMDA receptor 2 subunit control calpain-mediated cleavage of the NMDA receptor. J. Neurosci. 24, 11035–11045 (2004).

    Article  CAS  Google Scholar 

  34. 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).

    Article  CAS  Google Scholar 

  35. Costa-Mattioli, M. et al. Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature 436, 1166–1173 (2005).

    Article  CAS  Google Scholar 

  36. Kiyama, Y. et al. Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor epsilon1 subunit. J. Neurosci. 18, 6704–6712 (1998).

    Article  CAS  Google Scholar 

  37. Wattler, S., Kelly, M. & Nehls, M. Construction of gene targeting vectors from lambda KOS genomic libraries. Biotechniques 26 1150–6, 1158, 1160 (1999).

    Article  CAS  Google Scholar 

  38. Gold, S.J., Ni, Y.G., Dohlman, H.G. & Nestler, E.J. Regulators of G-protein signaling (RGS) proteins: region-specific expression of nine subtypes in rat brain. J. Neurosci. 17, 8024–8037 (1997).

    Article  CAS  Google Scholar 

  39. Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006).

    Article  CAS  Google Scholar 

  40. Nishi, A. et al. Regulation of DARPP-32 dephosphorylation at PKA- and Cdk5-sites by NMDA and AMPA receptors: distinct roles of calcineurin and protein phosphatase-2A. J. Neurochem. 81, 832–841 (2002).

    Article  CAS  Google Scholar 

  41. Powell, C.M. et al. The presynaptic active zone protein RIM1alpha is critical for normal learning and memory. Neuron 42, 143–153 (2004).

    Article  CAS  Google Scholar 

  42. Cooper, D.C., Chung, S. & Spruston, N. Output-mode transitions are controlled by prolonged inactivation of sodium channels in pyramidal neurons of subiculum. PLoS Biol. 3, e175 (2005).

    Article  Google Scholar 

  43. Itoh, K., Shimono, K. & Lemmon, V. Dephosphorylation and internalization of cell adhesion molecule L1 induced by theta burst stimulation in rat hippocampus. Mol. Cell. Neurosci. 29, 245–249 (2005).

    Article  CAS  Google Scholar 

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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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Authors and Affiliations

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Contributions

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.

Corresponding author

Correspondence to James A Bibb.

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The authors declare no competing financial interests.

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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