Research

1. Glutamate transporters & normal tension glaucoma (NTG)

Ischemic stress and glutamate neurotoxicity are implicated in a number of pathological states such as retinal artery occlusion and glaucoma. Glaucoma is one of the leading causes of irreversible blindness due to retinal ganglion cell (RGC) degeneration (Fig. 1). 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). Thus, understanding IOP-independent mechanisms of RGC loss is important. We previously reported that GLAST, a glial-type glutamate transporter located at Müller cells (Figure 1), plays an important role to control glutamate concentration in the retina (Figure 2) (Proc Natl Acad Sci USA, 1998). In addition, we recently found that GLAST-deficient mice demonstrate spontaneous RGC and optic nerve degeneration without elevated IOP (Figure 3) (Journal of Clinical Investigation, 2007). In GLAST-deficient mice, the glutathione level in Müller glia was decreased and administration of glutamate receptor blocker (memantine) prevented RGC loss. These findings suggest that glutamate transporters are necessary both to prevent excitotoxic retinal damage and to synthesize glutathione, a major cellular antioxidant and tri-peptide of glutamate, cysteine, and glycine. To our knowledge, GLAST-deficient mouse is the first animal model of NTG that offers a powerful system for investigating mechanisms of neurodegeneration in NTG and developing therapies directed at IOP-independent mechanisms of RGC loss.

Fig.1 Structure of the retina.

Fig.2 Regulation of glutamate concentration by glutamate transporter.

Fig.3 GLAST-deficient mouse as a first animal model of normal tension glaucoma.

2. Retinal development, degeneration & neurotrophins

Neurotrophins induce neural cell differentiation and control cell number during retinal development (Cell Death & Differentiation 2007; Genes & Development, 2007). In addition, exogenous neurotrophins can delay the process of photoreceptor degeneration in animal models of retinitis pigmentosa. We found that these neurotrophins protect photoreceptors, at least partly, through Müller glial cells (Figure 1). Müller cells, acting in response to NT-3 or NGF, respectively, increase or decrease their production of basic fibroblast growth factor (bFGF), which in turn results in either the protection or increased apoptosis of photoreceptor cells (Figure 4) (Neuron, 2000; Journal of Neuroscience, 2002). These observations implicate glial cells in the determination of neural cell survival, and suggest functional glial-neuronal cell interactions as new therapeutic targets for neurodegeneration. We are also interested in the effects of neurotrophins on other retinal diseases such as diabetic retinopathy and epiretinal membranes (Progress in Retinal and Eye Research, 2006).

Fig.4 Glia-neuron network during photoreceptor degeneration.

Staff

Publications

Selected articles

1. Namekata K, Harada C, Kohyama K, Matsumoto Y, Harada, T. Interleukin-1 stimulates glutamate uptake in glial cells by accelerating membrane trafficking of Na⁺/K⁺-ATPase via actin depolymerization. Molecular and Cellular Biology 28:3273-3280, 2008.
2. Harada T, Harada C, Nakamura K, Quah HA, Okumura A, Namekata K, Saeki T, Aihara M, Yoshida H, Mitani A, Tanaka K. The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma. Journal of Clinical Investigation 117:1763-1770, 2007.
3. Nakamura K, Namekata K, Harada C, Harada T. Intracellular sortilin expression pattern regulates proNGF-induced naturally occurring cell death during development. Cell Death & Differentiation 14:1552-1554, 2007.
4. Harada T, Harada C, Parada LF. Molecular regulation of visual system development: more than meets the eye. Genes & Development 21:367-378, 2007.
5. Harada C, Harada T, Nakamura K, Sakai Y, Tanaka K, Parada LF. Effect of p75NTR on the regulation of naturally occuring cell death and retinal ganglion cell number in the mouse eye. Developmental Biology 290:57-65, 2006.
6. Harada C, Nakamura K, Namekata K, Okumura A, Mitamura Y, Iizuka Y, Kashiwagi K, Yoshida K, Ohno S, Matsuzawa A, Tanaka K, Ichijo H, Harada T. Role of apoptosis signal-regulating kinase 1 in stress-induced neural cell apoptosis in vivo. American Journal of Pathology 168:261-269, 2006.
7. Harada C, Mitamura Y, Harada T. Role of cytokines and trophic factors in epiretinal membranes: involvement of signal transduction in glial cells. Progress in Retinal and Eye Research 25:149-164, 2006.
8. Harada T, Harada C, Kohsaka S, Wada E, Yoshida K, Ohno S, Mamada H, Tanaka K, Parada LF, Wada K. Microglia-Müller glia cell interactions control neurotrophic factor production during light-induced retinal degeneration. Journal of Neuroscience 22:9228-9236, 2002.
9. Harada T, Harada C, Nakayama N, Okuyama S, Yoshida K, Kohsaka S, Matsuda H, Wada K. Modification of glial-neuronal cell interactions prevents photoreceptor apoptosis during light-induced retinal degeneration. Neuron 26:533-541, 2000.
10. Harada T, Harada C, Watanabe M, Inoue Y, Sakagawa T, Nakayama N, Sasaki S, Okuyama S, Watase K, Wada K, Tanaka K. Functions of the two glutamate transporters GLAST and GLT-1 in the retina. Proc Natl Acad Sci USA 95:4663-4666, 1998.