Depression of retinal glutamate transporter function leads to elevated intravitreal glutamate levels and ganglion cell death.
OBJECTIVE
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; E:xcitatory A:mino A:cid T:ransporter; 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 ganglion cells.


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.
Vorwerk
C K
CK
Scheie Eye Institute, Philadelphia Veterans Administration, the University of Pennsylvania, Philadelphia 19104, USA.
Naskar
R
R
Schuettauf
F
F
Quinto
K
K
Zurakowski
D
D
Gochenauer
G
G
Robinson
M B
MB
Mackler
S A
SA
Dreyer
E B
EB
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000502:physiology; D027322:Amino Acid Transport System X-AG; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers / Q000737:chemistry; D003998:Dicarboxylic Acids / Q000494:pharmacology; D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid / Q000378:metabolism*; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors* / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000473:pathology*; D014822:Vitreous Body / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D017931:DNA Primers; D003998:Dicarboxylic Acids; D027342:Excitatory Amino Acid Transporter 2; D014179:Neurotransmitter Uptake Inhibitors; D016376:Oligonucleotides, Antisense; D011759:Pyrrolidines; D017981:Receptors, Neurotransmitter; D018698:Glutamic Acid; C020889:dihydrokainic acid; C083486:pyrrolidine-2,4-dicarboxylic acid; D007608:Kainic Acid