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Tumor necrosis factor-α modulates glutamate transport in the CNS and is a critical determinant of outcome from viral encephalomyelitis

Authors
Journal
Brain Research
0006-8993
Publisher
Elsevier
Publication Date
Volume
1263
Identifiers
DOI: 10.1016/j.brainres.2009.01.040
Keywords
  • Astrocyte
  • Tnf-α
  • Motor Neuron
  • Glt-1
  • Glutamate
  • Virus
Disciplines
  • Medicine

Abstract

Abstract Neuroadapted Sindbis virus (NSV) is a neuronotropic virus that causes a fulminant encephalomyelitis in susceptible mice due to death of motor neurons in the brain and spinal cord. We and others have found that uninfected motor neurons die in response to NSV infection, at least in part due to disrupted astrocytic glutamate transport, resulting in excitotoxic motor neuron death. Here, we examined the mechanisms of astrocyte dysregulation associated with NSV infection. Treatment of organotypic slice cultures with NSV results in viral replication, cell death, altered astrocyte morphology, and the downregulation of the astrocytic glutamate transporter, GLT-1. We have found that TNF-α can mediate GLT-1 downregulation. Furthermore, TNF-α deficient mice infected with NSV exhibit neither GLT-1 downregulation nor neuronal death of brainstem and cervical spinal cord motor neurons and have markedly reduced mortality. These findings have implications for disease intervention and therapeutic development for the prevention of CNS damage associated with inflammatory responses.

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