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Neuron. 2014 Mar 5;81(5):1070-83. doi: 10.1016/j.neuron.2014.01.022.

Memory enhancement by targeting Cdk5 regulation of NR2B.

Author information

  • 1Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA.
  • 3Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 4Department of Pharmacology, School of Medicine, Kurume University, Fukuoka 830-0011, Japan.
  • 5Cell Signaling Technology, CNS Development, Danvers, MA 01923, USA.
  • 6Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: james.bibb@utsouthwestern.edu.

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.

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Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24607229
[PubMed - indexed for MEDLINE]
PMCID:
PMC4010123
[Available on 2015/3/5]
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