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

Jessica Carmen, Jeffrey D Rothstein, Douglas A. Kerr

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)143-154
Number of pages12
JournalBrain Research
Volume1263
DOIs
StatePublished - Mar 31 2009

Fingerprint

Sindbis Virus
Encephalomyelitis
Motor Neurons
Glutamic Acid
Tumor Necrosis Factor-alpha
Down-Regulation
Virus Diseases
Astrocytes
Amino Acid Transport System X-AG
Brain Stem
Spinal Cord
Cell Death
Viruses
Mortality
Brain

Keywords

  • Astrocyte
  • GLT-1
  • Glutamate
  • Motor neuron
  • TNF-α
  • Virus

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

Tumor necrosis factor-α modulates glutamate transport in the CNS and is a critical determinant of outcome from viral encephalomyelitis. / Carmen, Jessica; Rothstein, Jeffrey D; Kerr, Douglas A.

In: Brain Research, Vol. 1263, 31.03.2009, p. 143-154.

Research output: Contribution to journalArticle

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