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Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways

Nature Neuroscience volume 5, pages 405414 (2002) | Download Citation

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Abstract

Here we report that synaptic and extrasynaptic NMDA (N-methyl-D-aspartate) receptors have opposite effects on CREB (cAMP response element binding protein) function, gene regulation and neuron survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have anti-apoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death. Specific blockade of extrasynaptic NMDA receptors may effectively prevent neuron loss following stroke and other neuropathological conditions associated with glutamate toxicity.

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Acknowledgements

We thank F. Arnold for help with the multi-electrode array recordings, and P. Vanhoutte and B. Wisden for discussion. This work was supported by the Medical Research Council, Clare College, Cambridge, and the Alexander von Humboldt Foundation.

Author information

Author notes

    • Yuko Fukunaga

    Present address: Membrane Dynamics Project, RIKEN, Harima Institute, Hyogo 679-5148, Japan

    • Hilmar Bading

    Present address: Department of Neurobiology, Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany

Affiliations

  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK

    • Giles E. Hardingham
    • , Yuko Fukunaga
    •  & Hilmar Bading

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The authors declare no competing financial interests.

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Correspondence to Hilmar Bading.

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https://doi.org/10.1038/nn835

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