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Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation
Hawasli AH, Benavides DR, Nguyen C, Kansy JW,
Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb
JA
Nat Neurosci. 2007 Jul;10(7):880-6.
Epub 2007 May 27
Learning is accompanied by modulation of
postsynaptic signal transduction pathways in neurons. Although
the neuronal protein kinase cyclin-dependent kinase 5 (Cdk5)
has been implicated in cognitive disorders, its role in
learning has been obscured by the perinatal lethality of
constitutive knockout mice. Here we report that conditional
knockout of Cdk5 in the adult mouse brain improved performance
in spatial learning tasks and enhanced hippocampal long-term
potentiation and NMDA receptor (NMDAR)-mediated excitatory
postsynaptic currents. Enhanced synaptic plasticity in Cdk5
knockout mice was attributed to reduced NR2B degradation,
which caused elevations in total, surface and synaptic NR2B
subunit levels and current through NR2B-containing NMDARs.
Cdk5 facilitated the degradation of NR2B by directly
interacting with both it and its protease, calpain. These
findings reveal a previously unknown mechanism by which Cdk5
facilitates calpain-mediated proteolysis of NR2B and may
control synaptic plasticity and
learning.
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