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The Journal of Neuroscience, April 26, 2006, 26(17):4509-4518; doi:10.1523/JNEUROSCI.0455-06.2006
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Cellular/Molecular
Preconditioning Doses of NMDA Promote Neuroprotection by Enhancing Neuronal Excitability
Francesc X. Soriano,1 *
Sofia Papadia,1 *
Frank Hofmann,2
Neil R. Hardingham,3
Hilmar Bading,2 and
Giles E. Hardingham1
1Centre for Neuroscience Research, University of Edinburgh, Edinburgh EH9 1QH, United Kingdom, 2Department of Neurobiology, Interdisciplinary Center for Neurosciences, D-69120 Heidelberg, Germany, and 3School of Biosciences, Cardiff University, Cardiff CF10 3US, United Kingdom
Correspondence should be addressed to Giles E. Hardingham, Centre for Neuroscience Research, University of Edinburgh, Summerhall Square, Edinburgh EH9 1QH, UK. Email: Giles.Hardingham{at}ed.ac.uk
Neuroprotection can be induced by low doses of NMDA, which activate both synaptic and extrasynaptic NMDA receptors. This is in apparent contradiction with our recent findings that extrasynaptic NMDA receptor signaling exerts a dominant inhibitory effect on prosurvival signaling from synaptic NMDA receptors. Here we report that exposure to low preconditioning doses of NMDA results in preferential activation of synaptic NMDA receptors because of a dramatic increase in action potential firing. Both acute and long-lasting phases of neuroprotection in the face of apoptotic or excitotoxic insults are dependent on this firing enhancement. Key mediators of synaptic NMDA receptor-dependent neuroprotection, phosphatidylinositol 3 kinase-Akt (PI3 kinase-Akt) signaling to Forkhead box subgroup O (FOXO) export and glycogen synthase kinase 3 (GSK3) inhibition and cAMP response element-binding protein-dependent (CREB-dependent) activation of brain-derived neurotrophic factor (BDNF), can be induced only by low doses of NMDA via this action potential-dependent route. In contrast, NMDA doses on the other side of the toxicity threshold do not favor synaptic NMDA receptor activation because they strongly suppress firing rates below baseline. The classic bell-shaped curve depicting neuronal fate in response to NMDA dose can be viewed as the net effect of two antagonizing (synaptic vs extrasynaptic) curves: via increased firing the synaptic signaling dominates at low doses, whereas firing becomes suppressed and extrasynaptic signaling dominates as the toxicity threshold is crossed.
Key words: apoptosis; calcium [Ca]; transcription; excitability; kinase; CREB; signal transduction; tolerance; NMDA receptor; neuroprotection; PI3 kinase
Received Feb. 1, 2006;
revised March 13, 2006;
accepted March 16, 2006.
Correspondence should be addressed to Giles E. Hardingham, Centre for Neuroscience Research, University of Edinburgh, Summerhall Square, Edinburgh EH9 1QH, UK. Email: Giles.Hardingham{at}ed.ac.uk
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