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

Nature Neuroscience volume 5, pages 405–414 (2002)Cite this article

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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Figure 1: Calcium entry through NMDA receptors rather than through L-type calcium channels is responsible for nuclear signaling to CREB and induction of CRE-dependent transcription in synaptically activated hippocampal neurons.
Figure 2: NMDA receptors activated by synaptic activity robustly induced BDNF expression.
Figure 3: Comparison of NMDA receptor–mediated calcium signals triggered by bursts of action potentials or by glutamate bath application.
Figure 4: Calcium flux through extrasynaptic NMDA receptors initiates a CREB shut-off signal and suppresses induction of BDNF expression.
Figure 5: Inhibition of the predominantly extrasynaptically localized NMDA receptor subunit NR2B with ifenprodil blocks the CREB shut-off process.
Figure 6: Extrasynaptic NMDA receptors mediate CREB shut-off induced by hypoxia/ischemia.
Figure 7: Extrasynaptic NMDA receptors are linked to mitochondrial dysfunction and neuronal death.
Figure 8: Stimulation of synaptic NMDA receptors is anti-apoptotic.

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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.

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Author notes

  1. Yuko Fukunaga

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

  2. Hilmar Bading

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

Authors and Affiliations

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

    Giles E. Hardingham, Yuko Fukunaga & Hilmar Bading

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Correspondence to Hilmar Bading.

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Hardingham, G., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 5, 405–414 (2002). https://doi.org/10.1038/nn835

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