Intrathecal infusion of a Ca(2+)-permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter, GLT-1 in a mutant SOD1 rat model of ALS.
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.
Yin
Hong Z
HZ
Department of Neurology, University of California, Irvine, CA 92697, USA.
Tang
Darryl T
DT
Weiss
John H
JH
D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D030801:Animals, Genetically Modified; D001253:Astrocytes / Q000187:drug effects*; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D009046:Motor Neurons / Q000187:drug effects*; D051381:Rats; D013096:Spermine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013482:Superoxide Dismutase / Q000235:genetics
D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; C067506:1-naphthylacetylspermine; D013096:Spermine; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
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