Ammonia downregulates GLAST mRNA glutamate transporter in rat astrocyte cultures.
Abnormalities in glutamate metabolism and glutamatergic neurotransmission appear to play an important role in the pathogenesis of hyperammonemia and hepatic encephalopathy. Previous studies from our laboratory have shown that treatment of cultured astrocytes with NH4Cl result in decreased glutamate uptake. To extend these observations, we performed a Northern blot analysis of the astroglial glutamate transporter GLAST (EAAT1) in NH4Cl-treated primary rat astrocyte cultures. Following treatment with 2, 5, 10 mM NH4Cl for 3 days, cortical astrocytes showed a 22, 29, 36% decrease in GLAST mRNA, respectively. Striatal astrocytes showed 25, 51, 50% reduction, while cerebellar cultures showed decrements of 18, 37, 38%. Similar decreases in GLAST mRNA were also observed after 1 day of ammonia treatment. These findings, together with recent reports on the reduction of the GLT-1 glutamate transporter in in vivo models of acute liver failure and hyperammonemia, strongly suggest that an abnormality in astroglial glutamate uptake constitutes a critical aspect in the pathogenesis of hepatic encephalopathy and other hyperammonemic conditions.
Zhou
B G
BG
Laboratory of Neuropathology, Veterans Administration Medical Center, University of Miami School of Medicine, Miami, FL 33101, USA.
Norenberg
M D
MD
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D027322:Amino Acid Transport System X-AG; D000641:Ammonia / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015152:Blotting, Northern; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D015536:Down-Regulation; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D012333:RNA, Messenger; D000641:Ammonia