Intracellular signalling mechanisms underlying memory enhancement
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.
Recently I characterized a novel NMDAR-associated mechanism that can be targeted to enhance memory. I found that NR2B is directly phosphorylated by the protein kinase cyclin-dependent kinase 5 (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 small interfering peptides (siP) increases NR2B surface levels and facilitates synaptic transmission. Accordingly, intra-hippocampal infusion of the NR2B-siP improved fear memory formation in vivo.
Taken together, these 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.
Date: 10 March 2016, 14:00 (Thursday, 8th week, Hilary 2016)
Venue: Sherrington Building, off Parks Road OX1 3PT
Venue Details: Sherrington Library, Sherrington Building, DPAG
Speakers: Speaker to be announced
Organising department: Department of Physiology, Anatomy and Genetics (DPAG)
Organiser: Professor Richard Wade-Martins (Professor of Molecular Neuroscience, University of Oxford)
Organiser contact email address:
Host: Professor Richard Wade-Martins (Professor of Molecular Neuroscience, University of Oxford)
Booking required?: Not required
Audience: Public
Editor: Victoria Bullett