Differential regulation of glutamate transporter subtypes by pro-inflammatory cytokine TNF-α in cortical astrocytes from a rat model of amyotrophic lateral sclerosis.
Dysregulation of the astroglial glutamate transporters GLAST and GLT-1 has been implicated in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) where a loss of GLT-1 protein expression and activity is reported. Furthermore, the two principal C-terminal splice variants of GLT-1 (namely GLT-1a and GLT-1b) show altered expression ratio in animal models of this disease. Considering the putative link between inflammation and excitotoxicity, we have here characterized the influence of TNF-α on glutamate transporters in cerebral cortical astrocyte cultures from wild-type rats and from a rat model of ALS (hSOD1G93A). Contrasting with the down-regulation of GLAST, a 72 h treatment with TNF-α substantially increased the expression of GLT-1a and GLT-1b in both astrocyte cultures. However, as the basal level of GLT-1a appeared considerably lower in hSOD1G93A astrocytes, its up-regulation by TNF-α was insufficient to recapitulate the expression observed in wild-type astrocytes. Also the glutamate uptake activity after TNF-α treatment was lower for hSOD1G93A astrocytes as compared to wild-type astrocytes. In the presence of the protein synthesis inhibitor cycloheximide, TNF-α did not influence GLT-1 isoform expression, suggesting an active role of dynamically regulated protein partners in the adaptation of astrocytes to the inflammatory environment. Confirming the influence of inflammation on the control of glutamate transmission by astrocytes, these results shed light on the regulation of glutamate transporter isoforms in neurodegenerative disorders.
Institute of Neuroscience, Group of Neuropharmacology, Université Catholique de Louvain, Brussels, Belgium.
Amélie O
AO
Dumont
Institute of Neuroscience, Group of Neuropharmacology, Université Catholique de Louvain, Brussels, Belgium.
Stéphanie
S
Goursaud
Institute of Neuroscience, Group of Neuropharmacology, Université Catholique de Louvain, Brussels, Belgium.
Nathalie
N
Desmet
Institute of Neuroscience, Group of Neuropharmacology, Université Catholique de Louvain, Brussels, Belgium.
Emmanuel
E
Hermans
D027322:Amino Acid Transport System X-AG / Q000235:genetics* / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000166:cytology; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D014176:Protein Biosynthesis / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D027322:Amino Acid Transport System X-AG; D016207:Cytokines; D020033:Protein Isoforms; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1