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Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors

Nature Neuroscience volume 6, pages 1039–1047 (2003)Cite this article

Abstract

CA1 pyramidal neurons degenerate after transient forebrain ischemia, whereas neurons in other regions of the hippocampus remain intact. Here we show that in rat hippocampal CA1 neurons, forebrain ischemia induces the phosphorylation of the N-methyl-D-aspartate (NMDA) receptor 2A subunit at Ser1232 (phospho-Ser1232). Ser1232 phosphorylation is catalyzed by cyclin-dependent kinase 5 (Cdk5). Inhibiting endogenous Cdk5, or perturbing interactions between Cdk5 and NR2A subunits, abolished NR2A phosphorylation at Ser1232 and protected CA1 pyramidal neurons from ischemic insult. Thus, we conclude that modulation of NMDA receptors by Cdk5 is the primary intracellular event underlying the ischemic injury of CA1 pyramidal neurons.

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Figure 1: Activation of Cdk5 after transient forebrain ischemia is associated with CA1 pyramidal cell death.
Figure 2: Inhibition of Cdk5 protects CA1 pyramidal neurons from ischemic insult.
Figure 3: MK-801 prevents CA1 pyramidal cell death but not Cdk5 activation.
Figure 4: Cdk5 enhances recombinant NMDA receptor currents by phosphorylating the NR2A subunit at Ser1232.
Figure 5: Inhibition of Cdk5 prevents the ischemia-induced increase of EPSCNMDA.
Figure 6: Expression of the C-terminal fragment of NR2A dissociates endogenous Cdk5 from the NMDA receptor complex.
Figure 7: Interrupting Cdk5–NMDA receptor interaction protects CA1 neurons from ischemic insult.
Figure 8: NBQX prevents Cdk5 activation and CA1 pyramidal cell death.

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Acknowledgements

This work was supported by grants (to Y.M.L.) from the Canadian Institute of Health Research, the Heart and Stroke Foundation (Canada), the Alberta Heritage Foundation for Medical Research, the Canada Foundation for Innovation and the Alberta Department of Innovation and Science. We thank K. Lukowiak for comments on the manuscript.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, University of Calgary, Calgary, T2N 4N1, Canada

    Jian Wang, ShuHong Liu, YangPing Fu & YouMing Lu

  2. Department of Biochemistry and Molecular Biology, Neuroscience Research Group, Faculty of Medicine, University of Calgary, Calgary, T2N 4N1, Canada

    Jerry H Wang

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Wang, J., Liu, S., Fu, Y. et al. Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors. Nat Neurosci 6, 1039–1047 (2003). https://doi.org/10.1038/nn1119

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