Journal
JOURNAL OF NEUROSCIENCE
Volume 28, Issue 44, Pages 11391-11400Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3708-08.2008
Keywords
inflammation; excitotoxicity; trauma; plasticity; neuroinflammation; neural-immune interaction; glia-neuron interactions
Categories
Funding
- National Institutes of Health [R01 NS38079]
- New York State CoRE (Center of Research Excellence)
- Christopher Reeve Foundation [BB-0204-2, R01 MH067931, F32 NS053059, F32 NS045468, F30 NS053185]
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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 alpha (TNF alpha) in vitro. This has potential relevance to several CNS disorders, because many pathological states have a neuroinflammatory component involving TNF alpha. However, TNF alpha-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 alpha, which produces specific trafficking of GluR2-lacking receptors which enhance excitotoxicity. To determine if TNF alpha-induced trafficking affects neuronal cell death, we sequestered TNF alpha after SCI using a soluble TNF alpha receptor, and significantly reduced both AMPAR trafficking and neuronal excitotoxicity in the injury penumbra. The data provide the first evidence linking rapid TNF alpha-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.
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