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Christian K. Vorwerk, Rita Naskar, Frank Schuettauf, Kristine Quinto, David Zurakowski, Gordon Gochenauer, Michael B. Robinson, Scott A. Mackler, Evan B. Dreyer; Depression of Retinal Glutamate Transporter Function Leads to Elevated Intravitreal Glutamate Levels and Ganglion Cell Death. Invest. Ophthalmol. Vis. Sci. 2000;41(11):3615-3621.
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purpose. Elevated levels of extracellular glutamate have been implicated in the
pathophysiology of neuronal loss in both central nervous system and
ophthalmic disorders, including glaucoma. This increase in glutamate
may result from a failure of glutamate transporters (molecules that
ordinarily regulate extracellular glutamate; Excitatory Amino Acid Transporter;
EAAT). Elevated glutamate levels can also lead to alterations in
glutamate receptor expression. It was hypothesized that
selective blockade of glutamate transporters would be toxic to retinal
methods. Glutamate transporters were blocked either pharmacologically or with
subtype-specific antisense oligonucleotides against EAAT1. Glutamate
levels, transporter levels and ganglion cell survival were assayed.
results. Pharmacological inhibition of glutamate transporters with either an
EAAT2 specific inhibitor or a nonspecific inhibitor of all the subtypes
of transporters was toxic to ganglion cells. Treatment with
oligonucleotides against the glutamate transporter EAAT1 decreased the
levels of expression of the transporter, increased vitreal glutamate,
and was toxic to ganglion cells.
conclusions. These results demonstrate that normal function of EAAT1 and EAAT2 is
necessary for retinal ganglion cell survival and plays an important
role in retinal excitotoxicity. Manipulation of retinal glutamate
transporter expression may become a useful tool in understanding
retinal neuronal loss.
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