Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation.
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.
Hawasli
Ammar H
AH
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.
Benavides
David R
DR
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.
Nguyen
Chan
C
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.
Kansy
Janice W
JW
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.
Hayashi
Kanehiro
K
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.
Chambon
Pierre
P
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch Cedex, Centre Universitaire de Strasbourg, France.
Greengard
Paul
P
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
Powell
Craig M
CM
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.|Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.
Cooper
Donald C
DC
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.
Bibb
James A
JA
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.
D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D047468:Immunoprecipitation; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D051360:Cyclin-Dependent Kinase 5