Concurrent downregulation of a glutamate transporter and receptor in glaucoma

PURPOSE. Elevated levels of extracellular glutamate have been implicated in the pathophysiology of neuronal loss in both central nervous system and op hthalmic disorders, including glaucoma. This increase in glutamate may resu lt from a failure of glutamate transporters, which are molecules that: ordi narily regulate extracellular glutamate. Elevated glutamate levels can also lead to a perturbation in glutamate receptors. The hypothesis for the curr ent study was that glutamate transporters and/or receptors are altered in h uman glaucoma. METHODS. Immunohistochemical analyses of human eyes with glaucoma and contr ol eyes were performed to evaluate glutamate receptors and transporters. Th ese molecules were also assayed in rat eyes injected with glial-derived neu rotrophic factor (GDNF). RESULTS. Glaucomatous eyes had decreased levels of both the glutamate trans porter, excitatory amino acid transporter (EAAT)-1, and the glutamate recep tor subunit N-methyl-D-aspartate (NMDA)-R1. Eyes treated with GDNF had elev ated levels of both EAAT1 and NMDAR1. CONCLUSIONS. The loss of EAAT1 in glaucoma may account for the elevated lev el of glutamate found in glaucomatous vitreous and lead to a compensatory d ownregulation of NMDAR1. Inasmuch as GDNF can increase levels of both EAAT1 and NMDAR1, it may be a useful therapeutic approach to restore homeostatic levels of these in glaucoma.