TY - JOUR
T1 - Memory enhancement by targeting Cdk5 regulation of NR2B
AU - Plattner, Florian
AU - Hernández, Adan
AU - Kistler, Tara M.
AU - Pozo, Karine
AU - Zhong, Ping
AU - Yuen, Eunice Y.
AU - Tan, Chunfeng
AU - Hawasli, Ammar H.
AU - Cooke, Sam F.
AU - Nishi, Akinori
AU - Guo, Ailan
AU - Wiederhold, Thorsten
AU - Yan, Zhen
AU - Bibb, James A.
N1 - 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).
PY - 2014/3/5
Y1 - 2014/3/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84895438578&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2014.01.022
DO - 10.1016/j.neuron.2014.01.022
M3 - Article
C2 - 24607229
AN - SCOPUS:84895438578
VL - 81
SP - 1070
EP - 1083
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 5
ER -