KNOCKOUT OF GLUTAMATE TRANSPORTERS REVEALS A MAJOR ROLE FOR ASTROGLIAL TRANSPORT IN EXCITOTOXICITY AND CLEARANCE OF GLUTAMATE

Three glutamate transporters have been identified in rat, including as troglial transporters GLAST and GLT-1 and a neuronal transporter EAAC1 . Here we demonstrate that inhibition of the synthesis of each glutama te transporter subtype using chronic antisense oligonucleotide adminis tration, in vitro and in vivo, selectively and specifically reduced th e protein expression and function of glutamate transporters. The loss of glial glutamate transporters GLAST or GLT-1 produced elevated extra cellular glutamate levels, neurodegeneration characteristic of excitot oxicity, and a progressive paralysis. The loss of the neuronal glutama te transporter EAAC1 did not elevate extracellular glutamate in the st riatum but did produce mild neurotoxicity and resulted in epilepsy. Th ese studies suggest that glial glutamate transporters provide the majo rity of functional glutamate transport and are essential for maintaini ng low extracellular glutamate and for preventing chronic glutamate ne urotoxicity.