Knockout of Glutamate Transporters Reveals a Major Role for Astroglial Transport in Excitotoxicity and Clearance of Glutamate

TLDR

Three glutamate transporters have been identified in rats: astroglial GLAST and GLT‑1 and neuronal EAAC1. We inhibited synthesis of each transporter subtype with chronic antisense oligonucleotides in vitro and in vivo, selectively reducing their protein expression and function. Loss of glial transporters GLAST or GLT‑1 raised extracellular glutamate, triggered excitotoxic neurodegeneration and progressive paralysis, whereas loss of neuronal EAAC1 did not raise striatal glutamate but caused mild neurotoxicity and epilepsy; these results show that glial transporters dominate glutamate clearance and are essential for preventing chronic neurotoxicity.

Abstract

Three glutamate transporters have been identified in rat, including astroglial transporters GLAST and GLT-1 and a neuronal transporter EAAC1. Here we demonstrate that inhibition of the synthesis of each glutamate transporter subtype using chronic antisense oligonucleotide administration, in vitro and in vivo, selectively and specifically reduced the protein expression and function of glutamate transporters. The loss of glial glutamate transporters GLAST or GLT-1 produced elevated extracellular glutamate levels, neurodegeneration characteristic of excitotoxicity, and a progressive paralysis. The loss of the neuronal glutamate transporter EAAC1 did not elevate extracellular glutamate in the striatum but did produce mild neurotoxicity and resulted in epilepsy. These studies suggest that glial glutamate transporters provide the majority of functional glutamate transport and are essential for maintaining low extracellular glutamate and for preventing chronic glutamate neurotoxicity.