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.
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Plattner
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Adan
authors.initials: A
authors.lastname: Hernández
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Kistler
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Karine
authors.initials: K
authors.lastname: Pozo
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhong
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Yuen
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Tan
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ammar H
authors.initials: AH
authors.lastname: Hawasli
authors.affiliation: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sam F
authors.initials: SF
authors.lastname: Cooke
authors.affiliation: Department of Pharmacology, School of Medicine, Kurume University, Fukuoka 830-0011, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
authors.affiliation: Cell Signaling Technology, CNS Development, Danvers, MA 01923, USA.
authors.forename: Ailan
authors.initials: A
authors.lastname: Guo
authors.affiliation: Cell Signaling Technology, CNS Development, Danvers, MA 01923, USA.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wiederhold
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department 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.
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000166:cytology; D008297:Male; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; C495907:Cdk5 protein, rat