@article{5c7d58beb4c24417a323d5b6857dc7b8,
title = "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.",
author = "Hawasli, {Ammar H.} and Benavides, {David R.} and Chan Nguyen and Kansy, {Janice W.} and Kanehiro Hayashi and Pierre Chambon and Paul Greengard and Powell, {Craig M.} and Cooper, {Donald C.} and Bibb, {James A.}",
note = "Funding Information: 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).",
year = "2007",
month = jul,
day = "8",
doi = "10.1038/nn1914",
language = "English (US)",
volume = "10",
pages = "880--886",
journal = "Nature neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "7",
}