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The Journal of Neuroscience, October 29, 2008, 28(44):11391-11400; doi:10.1523/JNEUROSCI.3708-08.2008

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Development/Plasticity/Repair
Cell Death after Spinal Cord Injury Is Exacerbated by Rapid TNF-Induced Trafficking of GluR2-Lacking AMPARs to the Plasma Membrane

Adam R. Ferguson,¹ Randolph N. Christensen,⁴ John C. Gensel,³ Brandon A. Miller,^1,2 Fang Sun,⁶ Eric C. Beattie,⁵ Jacqueline C. Bresnahan,¹ and Michael S. Beattie¹

¹Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94110, ²Department of Neuroscience and ³Department of Molecular Virology, Immunology, and Medical Genetics, Center for Brain and Spinal Repair, The Ohio State University, Columbus, Ohio 43210, ⁴Department of Biology, Coe College, Cedar Rapids, Iowa 52402, ⁵Department of Neurosciences, California Pacific Medical Center Research Institute, San Francisco, California 94107, and ⁶Neurology, Harvard University, Children's Hospital, Boston, Massachusetts 02115

Correspondence should be addressed to Dr. Michael S. Beattie, Department of Neurological Surgery, Brain and Spinal Injury Center, University of California, San Francisco, 1001 Potrero Avenue, Building 1, Room 101, San Francisco, CA 94110. Email: Michael.Beattie{at}ucsf.edu

Glutamate, the major excitatory neurotransmitter in the CNS, is implicated in both normal neurotransmission and excitotoxicity. Numerous in vitro findings indicate that the ionotropic glutamate receptor, AMPAR, can rapidly traffic from intracellular stores to the plasma membrane, altering neuronal excitability. These receptor trafficking events are thought to be involved in CNS plasticity as well as learning and memory. AMPAR trafficking has recently been shown to be regulated by glial release of the proinflammatory cytokine tumor necrosis factor (TNF) in vitro. This has potential relevance to several CNS disorders, because many pathological states have a neuroinflammatory component involving TNF. However, TNF-induced trafficking of AMPARs has only been explored in primary or slice cultures and has not been demonstrated in preclinical models of CNS damage. Here, we use confocal and image analysis techniques to demonstrate that spinal cord injury (SCI) induces trafficking of AMPARs to the neuronal membrane. We then show that this effect is mimicked by nanoinjections of TNF, which produces specific trafficking of GluR2-lacking receptors which enhance excitotoxicity. To determine if TNF-induced trafficking affects neuronal cell death, we sequestered TNF after SCI using a soluble TNF receptor, and significantly reduced both AMPAR trafficking and neuronal excitotoxicity in the injury penumbra. The data provide the first evidence linking rapid TNF-induced AMPAR trafficking to early excitotoxic secondary injury after CNS trauma in vivo, and demonstrate a novel way in which pathological states hijack mechanisms involved in normal synaptic plasticity to produce cell death.

Key words: inflammation; excitotoxicity; trauma; plasticity; neuroinflammation; neural–immune interaction; glia–neuron interactions

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Received Aug. 4, 2008; accepted Sept. 23, 2008.

Correspondence should be addressed to Dr. Michael S. Beattie, Department of Neurological Surgery, Brain and Spinal Injury Center, University of California, San Francisco, 1001 Potrero Avenue, Building 1, Room 101, San Francisco, CA 94110. Email: Michael.Beattie{at}ucsf.edu

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