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.

Mice lacking either bombesin receptor subtype (BRS)-3 or gastrin-releasing peptide receptor (GRP-R) exhibit feeding abnormalities. However, it is unclear how these receptors are associated with feeding regulation. In BRS-3-deficient mice, we found hyperphagia, subsequent hyperleptinemia, and brain leptin resistance that occurred after the onset of obesity. To explore the cause of this phenomenon, we examined changes in feeding responses to appetite-related neuropeptides in BRS-3-deficient, GRP-R-deficient, and wild-type littermate mice. Among orexigenic neuropeptides, the hyperphagic response to melanin-concentrating hormone (MCH) was significantly enhanced in BRS-3-deficient mice but not in GRP-R-deficient mice. In addition, the levels of MCH-R and prepro-MCH mRNAs in the hypothalamus of BRS-3-deficient mice were significantly more elevated than those of wild-type littermates. There was no significant difference in feeding between BRS-3-deficient and wild-type littermate mice after treatment with bombesin (BN), although the hypophagic response to low-dose BN was significantly suppressed in the GRP-R-deficient mice. These results suggest that upregulation of MCH-R and MCH triggers hyperphagia in BRS-3-deficient mice. From these results, we assume that the BRS-3 gene deletion upsets the mechanism by which leptin decreases the expression of MCH-R and that this effect may be mediated through neural networks independent of BN-related peptides such as GRP-R. Diabetes 53: 570 -576, 2004