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

Ammar H. Hawasli, David R. Benavides, Chan Nguyen, Janice W. Kansy, Kanehiro Hayashi, Pierre Chambon, Paul Greengard, Craig M. Powell, Donald C. Cooper, James A. Bibb

Research output: Contribution to journalArticle

218 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)880-886
Number of pages7
JournalNature Neuroscience
Volume10
Issue number7
DOIs
Publication statusPublished - 2007 Jul 8
Externally publishedYes

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Cyclin-Dependent Kinase 5
Neuronal Plasticity
N-Methyl-D-Aspartate Receptors
Learning
Calpain
Knockout Mice
Long-Term Potentiation
Excitatory Postsynaptic Potentials
Protein Kinases
Proteolysis
Signal Transduction
Peptide Hydrolases
Neurons
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Hawasli, A. H., Benavides, D. R., Nguyen, C., Kansy, J. W., Hayashi, K., Chambon, P., ... Bibb, J. A. (2007). Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nature Neuroscience, 10(7), 880-886. https://doi.org/10.1038/nn1914

Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. / Hawasli, Ammar H.; Benavides, David R.; Nguyen, Chan; Kansy, Janice W.; Hayashi, Kanehiro; Chambon, Pierre; Greengard, Paul; Powell, Craig M.; Cooper, Donald C.; Bibb, James A.

In: Nature Neuroscience, Vol. 10, No. 7, 08.07.2007, p. 880-886.

Research output: Contribution to journalArticle

Hawasli, AH, Benavides, DR, Nguyen, C, Kansy, JW, Hayashi, K, Chambon, P, Greengard, P, Powell, CM, Cooper, DC & Bibb, JA 2007, 'Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation', Nature Neuroscience, vol. 10, no. 7, pp. 880-886. https://doi.org/10.1038/nn1914
Hawasli, Ammar H. ; Benavides, David R. ; Nguyen, Chan ; Kansy, Janice W. ; Hayashi, Kanehiro ; Chambon, Pierre ; Greengard, Paul ; Powell, Craig M. ; Cooper, Donald C. ; Bibb, James A. / Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. In: Nature Neuroscience. 2007 ; Vol. 10, No. 7. pp. 880-886.
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