Journal
EXPERIMENTAL NEUROLOGY
Volume 238, Issue -, Pages 93-102Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2012.08.004
Keywords
Tumor necrosis factor-alpha; Amyotrophic lateral sclerosis; ALS; AMPA; Ca2+ permeable AMPA receptors; Slice culture; Motor neuron; Protein kinase A; Phosphatidylinositol 3 kinase
Categories
Funding
- NIH [NS36548, NS065219]
- Muscular Dystrophy Association
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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-alpha). TNF-alpha has complex effects on neurons, one of which is to trigger rapid membrane insertion of alpha-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-alpha 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-alpha 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-alpha, or of the glutamate uptake blocker, trans-pyrrolidine-2,4-dicarboxylic acid (PDC) to the cultures for 48 h resulted in little MN injury. However, when combined, TNF-alpha + 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-alpha 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. (C) 2012 Elsevier Inc. All rights reserved.
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