@article{49067faa0c7d4ea58a84ca30668c9893,
title = "Memory enhancement by targeting Cdk5 regulation of NR2B",
abstract = "Many psychiatric and neurological disorders are characterized by learning and memory deficits, for which cognitive enhancement is considered a valid treatment strategy. The N-methyl-D-aspartate receptor (NMDAR) is a prime target for the development of cognitive enhancers because of its fundamental role in learning and memory. In particular, the NMDAR subunit NR2B improves synaptic plasticity and memory when overexpressed in neurons. However, NR2B regulation is not well understood and no therapies potentiating NMDAR function have been developed. Here, we show that serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5). Cdk5-dependent NR2B phosphorylation is regulated by neuronal activity and controls the receptor's cell surface expression. Disrupting NR2B-Cdk5 interaction via a small interfering peptide (siP) increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation in vivo. Our results reveal a regulatory mechanism critical to NR2B function that can be targeted for the development of cognitive enhancers.",
author = "Florian Plattner and Adan Hern{\'a}ndez and Kistler, {Tara M.} and Karine Pozo and Ping Zhong and Yuen, {Eunice Y.} and Chunfeng Tan and Hawasli, {Ammar H.} and Cooke, {Sam F.} and Akinori Nishi and Ailan Guo and Thorsten Wiederhold and Zhen Yan and Bibb, {James A.}",
note = "Funding Information: We thank J. Rush (Cell Signaling Technologies) for mass spectroscopy analysis, A. Mussachio and M. Mapelli (European Institute of Oncology, Milan, Italy) for recombinant Cdk5/p25, U. Bayer (University of Colorado Denver) for the NR2B plasmid, H. Ball (UTSW Protein Technology Center) for peptide synthesis, P. Sykes (Charles River) for cannulated rats, S. Birnbaum for help with behavioral experiments, K. Richter and Pfizer, Inc. for CP68130, C. Hebel (LC Sciences) for peptide array analyses, S. Vicini (Georgetown University) for the GFP-NR2B plasmid, C. Castro, G. Mettlach, and S. Saldana for technical assistance, and T.V.P. Bliss for support. This work was supported by basic science training program T32-DA7290 in drug abuse (T.M.K.); and National Institutes of Health grants to Z.Y. (MH084233, MH085774), Yale/NIDA Neuroproteomics Center (DA018343), and J.A.B. (MH079710, MH083711, DA016672, DA033485, NS073855). ",
year = "2014",
month = mar,
day = "5",
doi = "10.1016/j.neuron.2014.01.022",
language = "English (US)",
volume = "81",
pages = "1070--1083",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "5",
}