Wolfson Institute for Biomedical Research
WIBR Seminar
‘Memory Enhancement by Targeting
Cdk5 Regulation
of NR2B’
Dr Florian Plattner
Department of Psychiatry
UT Southwestern Medical Center
Dallas, Texas, USA
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 a nd hence may serve as the basis for the
development of more effective therapeutics for memory impairment as well as age-dependent cognitive
decline.
Friday 26th June 2015 4pm
The Wolfson Institute for Biomedical Research
st
1 Floor Cruciform Building, Cruciform Café
Gower Street
London, WC1E 6BT
www.ucl.ac.uk/wibr