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Florian Plattner

Dr Florian Plattner


WIBR Seminar

'Memory Enhancement by Targeting Cdk5 Regulation of NR2B'

Dr Florian Plattner

florian-plattner-image

(Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas, USA

Host: professor John Hardy

Florian Plattner1*, Adan Hernandéz1*, Tara Kistler1*, Karine Pozo1, Eunice Y. Yuen2, Chunfeng Tan1, Akinori Nishi3, Thorsten Wiederhold4, Zhen Yan2, James A. Bibb1, 5, 6

1Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, 2Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, 3Department of Pharmacology, Kurume University School of Medicine, Fukuoka, Japan, 3Cell Signaling Technology, CNS Development, Danvers, MA 01923, 5Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, 6Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390.

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 due to its fundamental role in mnemonic functions. In particular, the NMDAR subunit NR2B has been found to improve synaptic plasticity and memory, when over-expressed in glutamatergic neurons. However, NR2B regulation is not well understood and no therapies potentiating NR2B function have been developed.

Novel phosphorylation sites of the protein kinase cyclin-dependent kinase 5 (Cdk5) on NR2B were identified employing a PhosphoScan approach. The physiological neuronal function of these sites was evaluated using primary hippocampal neuron cultures, acute hippocampal slice pharmacology and electrophysiological characterization. Based on the sequence surrounding the novel Cdk5 sites, small interfering peptides (siP) were developed that selectively disrupt the protein-protein interaction between NR2B and Cdk5. The functionality of the siP was characterized in vitro using biochemical and electrophysiological analyses and in vivo by testing their effect on contextual fear conditioning, a hippocampus-dependent learning task.

Here, we show that NR2B is directly phosphorylated by Cdk5 within its carboxy-terminal tail. Cdk5-dependent phosphorylation of NR2B is regulated by neuronal activity and regulates the receptor's cell surface expression. Disrupting the interaction between NR2B and Cdk5 with siP increases NR2B surface levels and facilitates synaptic transmission. Accordingly, intra-hippocampal infusion of the siP improved fear memory formation in vivo.

Taken together, our results reveal a novel molecular mechanism critically regulating NR2B function via Cdk5. A small molecule targeting this mechanism acted as a cognitive enhancer and hence may serve as the basis for the development of more effective therapeutics for memory impairment as well as age-dependent cognitive decline.


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Date: Friday 26th June 2015
Time: 4pm (please arrive 15 mins before start) 
Venue: Cruciform Café, 1st Floor Cruciform Building, Gower Street, UCL, WC1E 6BT
Refreshments will be provided