Article abstract


Nature Neuroscience 10, 880 - 886 (2007)
Published online: 27 May 2007 | doi:10.1038/nn1914

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

Ammar H Hawasli1,5, David R Benavides1,5, Chan Nguyen1, Janice W Kansy1, Kanehiro Hayashi1, Pierre Chambon2, Paul Greengard3, Craig M Powell1,4, Donald C Cooper1 & James A Bibb1


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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  1. Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.
  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch Cedex, Centre Universitaire de Strasbourg, France.
  3. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
  4. Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.
  5. These authors contributed equally to this work.

Correspondence to: James A Bibb1 e-mail: james.bibb@utsouthwestern.edu

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