Journal
EXPERIMENTAL NEUROLOGY
Volume 207, Issue 2, Pages 177-185Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2007.07.011
Keywords
amyotrophic lateral sclerosis; G93A; excitotoxicity; EAAT2; motor neuron; 3-nitrotyrosine; 1-naphthyl acetylspermine
Categories
Funding
- NINDS NIH HHS [R01 NS036548-06, R01 NS036548, R01 NS036548-05A2, NS36548] Funding Source: Medline
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Elevated extracellular glutamate, resulting from a loss of astrocytic glutamate transport capacity, may contribute to excitotoxic motor neuron (MN) damage in ALS. Accounting for their high excitotoxic vulnerability, MNs possess large numbers of unusual Ca(2+)-permeable AMPA channels (Ca-AMPA channels), the activation of which triggers mitochondrial Ca (2+) overload and strong reactive oxygen species (ROS) generation. However, the causes of the astrocytic glutamate transport loss remain unexplained. To assess the role of Ca-AMPA channels on the evolution of pathology in vivo, we have examined effects of prolonged intrathecal infusion of the Ca-AMPA channel blocker, 1-naphthyl acetylspermine (NAS), in G93A transgenic rat models of ALS. In wild-type animals, immunoreactivity for the astrocytic glutamate transporter, GLT-1, was particularly strong around ventral horn MNs. However, a marked loss of ventral horn GLT-1 was observed, along with substantial MN damage, prior to onset of symptoms (90- 100 days) in the G93A rats. Conversely, labeling with the oxidative marker, nitrotyrosine, was increased in the neuropil surrounding MNs in the transgenic animals. Compared to sham-treated G93A animals, 30-day NAS infusions (starting at 67 +/- 2 days of age) markedly diminished the loss of both MNs and of astrocytic GLT-1 labeling. These observations are compatible with the hypothesis that activation of Ca-AMPA channels on MNs contributes, likely in part through oxidative mechanisms, to loss of glutamate transporter in surrounding astrocytes. (C) 2007 Elsevier Inc. All rights reserved.
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