TNF-α triggers rapid membrane insertion of Ca2+ permeable AMPA receptors into adult motor neurons and enhances their susceptibility to slow excitotoxic injury

Hong Z. Yin, Cheng I. Hsu, Stephen Yu, Shyam Rao, Linda S. Sorkin, John H. Weiss

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Excitotoxicity (caused by over-activation of glutamate receptors) and inflammation both contribute to motor neuron (MN) damage in amyotrophic lateral sclerosis (ALS) and other diseases of the spinal cord. Microglial and astrocytic activation in these conditions results in release of inflammatory mediators, including the cytokine, tumor necrosis factor-alpha (TNF-α). TNF-α has complex effects on neurons, one of which is to trigger rapid membrane insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamate receptors, and in some cases, specific insertion of GluA2 lacking, Ca2+ permeable AMPA receptors (Ca-perm AMPAr). In the present study, we use a histochemical stain based upon kainate stimulated uptake of cobalt ions ("Co2+ labeling") to provide the first direct demonstration of the presence of substantial numbers of Ca-perm AMPAr in ventral horn MNs of adult rats under basal conditions. We further find that TNF-α exposure causes a rapid increase in the numbers of these receptors, via a phosphatidylinositol 3 kinase (PI3K) and protein kinase A (PKA) dependent mechanism. Finally, to assess the relevance of TNF-α to slow excitotoxic MN injury, we made use of organotypic spinal cord slice cultures. Co2+ labeling revealed that MNs in these cultures possess Ca-perm AMPAr. Addition of either a low level of TNF-α, or of the glutamate uptake blocker, trans-pyrrolidine-2,4-dicarboxylic acid (PDC) to the cultures for 48h resulted in little MN injury. However, when combined, TNF-α+PDC caused considerable MN degeneration, which was blocked by the AMPA/kainate receptor blocker, 2,3-Dihydroxy-6-nitro-7-sulfamoylbenzo (F) quinoxaline (NBQX), or the Ca-perm AMPAr selective blocker, 1-naphthyl acetylspermine (NASPM). Thus, these data support the idea that prolonged TNF-α elevation, as may be induced by glial activation, acts in part by increasing the numbers of Ca-perm AMPAr on MNs to enhance injurious excitotoxic effects of deficient astrocytic glutamate transport.

Original languageEnglish (US)
Pages (from-to)93-102
Number of pages10
JournalExperimental Neurology
Volume238
Issue number2
DOIs
StatePublished - Dec 1 2012
Externally publishedYes

Keywords

  • ALS
  • AMPA
  • Amyotrophic lateral sclerosis
  • Ca permeable AMPA receptors
  • Motor neuron
  • Phosphatidylinositol 3 kinase
  • Protein kinase A
  • Slice culture
  • Tumor necrosis factor-alpha

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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