The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma
Takayuki Harada, … , Akira Mitani, Kohichi Tanaka
Takayuki Harada, … , Akira Mitani, Kohichi Tanaka
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1763-1770. https://doi.org/10.1172/JCI30178.
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The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma

Abstract

Glaucoma, a progressive optic neuropathy due to retinal ganglion cell (RGC) degeneration, is one of the leading causes of irreversible blindness. Although glaucoma is often associated with elevated intraocular pressure (IOP), IOP elevation is not detected in a significant subset of glaucomas, such as normal tension glaucoma (NTG). Moreover, in some glaucoma patients, significant IOP reduction does not prevent progression of the disease. Thus, understanding IOP-independent mechanisms of RGC loss is important. Here, we show that mice deficient in the glutamate transporters GLAST or EAAC1 demonstrate spontaneous RGC and optic nerve degeneration without elevated IOP. In GLAST-deficient mice, the glutathione level in Müller glia was decreased; administration of glutamate receptor blocker prevented RGC loss. In EAAC1-deficient mice, RGCs were more vulnerable to oxidative stress. These findings suggest that glutamate transporters are necessary both to prevent excitotoxic retinal damage and to synthesize glutathione, a major cellular antioxidant and tripeptide of glutamate, cysteine, and glycine. We believe these mice are the first animal models of NTG that offer a powerful system for investigating mechanisms of neurodegeneration in NTG and developing therapies directed at IOP-independent mechanisms of RGC loss.

Authors

Takayuki Harada, Chikako Harada, Kazuaki Nakamura, Hun-Meng A. Quah, Akinori Okumura, Kazuhiko Namekata, Tadashiro Saeki, Makoto Aihara, Hiroshi Yoshida, Akira Mitani, Kohichi Tanaka

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Figure 5

Optic nerve degeneration and normal IOP in glutamate transporter mutant mice.

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Optic nerve degeneration and normal IOP in glutamate transporter mutant ...
(A and B) Optic nerve atrophy in 8-month-old GLAST–/– mice. In WT mice (A), the nasal and temporal nerve fibers (arrows) are beneath the internal limiting membrane (arrowhead) and enter a well-formed optic nerve (N). In GLAST–/– mice (B), the nerve fiber layer has become thin and almost absent as it enters the nerve (bold arrows). Cupping extends to the posterior aspect of the inner retinal layer (arrowheads). (C and D) Thinning of optic nerve is apparent in GLAST–/– (D) compared with WT (C) mice. (E and F) Staining of semithin sections with toluidine blue reveals the presence of abnormally dark axonal profiles (arrowheads) and decline of axons in GLAST–/– (F) compared with WT (E) mice. (G and H) Aqueous humor drainage structures in WT (G) and GLAST–/– (H) mice. Iridocorneal angle in GLAST–/– mice is normal with an obvious Schlemm’s canal (arrow) and trabecular meshwork (asterisk) compared with those in WT mice. The angle recess between the cornea (C) and iris is wide open. (I) IOP of young (4 weeks old) and adult (9–11 months old) mice. Sample numbers are indicated in parentheses. Scale bar: 200 μm (A, B, G, and H); 130 μm (C and D); 9 μm (E and F).