Memory enhancement by targeting Cdk5 regulation of NR2B

Florian Plattner, Adan Hernández, Tara M. Kistler, Karine Pozo, Ping Zhong, Eunice Y. Yuen, Chunfeng Tan, Ammar H. Hawasli, Sam F. Cooke, Akinori Nishi, Ailan Guo, Thorsten Wiederhold, Zhen Yan, James A. Bibb

Research output: Contribution to journalArticle

78 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1070-1083
Number of pages14
JournalNeuron
Volume81
Issue number5
DOIs
StatePublished - Mar 5 2014

ASJC Scopus subject areas

  • Neuroscience(all)

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    Plattner, F., Hernández, A., Kistler, T. M., Pozo, K., Zhong, P., Yuen, E. Y., Tan, C., Hawasli, A. H., Cooke, S. F., Nishi, A., Guo, A., Wiederhold, T., Yan, Z., & Bibb, J. A. (2014). Memory enhancement by targeting Cdk5 regulation of NR2B. Neuron, 81(5), 1070-1083. https://doi.org/10.1016/j.neuron.2014.01.022