glaucoma (Fig. 3) (Nakazawa et al., 2006). It is important to further evaluate and understand any pathogenic role of oligodendrocytes in glaucoma.

Other changes occur in the retina in glaucoma

PERG and complement

In addition to the optic nerve, changes within the retina must be considered in glaucoma. Recent studies show that PERG is greatly reduced early in DBA/2J glaucoma (Howell et al., 2007). Although the mechanisms of PERG attenuation are not known, they may involve direct changes within the retina. The complement pathway has been implicated in glaucoma and C1q, the initiating protein in

the classical complement cascade, is upregulated in aged DBA/2J mice compared to young controls (Stasi et al., 2006; Steele et al., 2006). In an extensive microarray study, we have shown that a variety of complement genes, including C1q and C3, are upregulated early in DBA/2J glaucoma prior to significant RGC death or axon degeneration (Howell, Libby, and John, in preparation). We have also shown that C1q is localized to RGC synapses in the IPL early in glaucoma (Stevens et al., 2007). Mice deficient in C1q or C3 exhibit large sustained defects in synapse elimination during retinal development (Stevens et al., 2007). We have experiments underway to functionally test the role of the complement system in glaucoma, with DBA/2J mice deficient in C1q, C3, or C3R.

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Dendrites and neurofilament accumulation

Early dendrite changes have been found in primate glaucoma (Weber et al., 1998). In glaucomatous mice, some surviving RGCs also have abnormal dendrite morphology (Jakobs et al., 2005). These RGCs show a loss of second and higher order dendrites with only a few and short third-order dendrites remaining (Fig. 4). In addition, some RGCs show the accumulation of nonphosphorylated neurofilament. These cells appear to represent a ‘‘remodeled’’ stable state and persist for some time prior to cell death. Similar cells would be potential targets for therapeutic rescue in human glaucoma.

Mu¨ller glia and ceruloplasmin

Although further experiments are needed to determine their importance, several other changes are reported in retinas of DBA/2J mice. On the basis of the increase in the intermediate filaments GFAP and Vimentin, Mu¨ller glia become activated in glaucoma (Xue et al., 2006; Inman and

Horner, 2007). Ceruloplasmin (Cp) expression (both protein and mRNA) increases locally in Mu¨ller glia cells and in their end feet in the inner limiting membrane in glaucomatous DBA/2J eyes. Cp expression also increases in human and primate glaucomas (Stasi et al., 2007). The authors suggest Cp, a known stress response protein (Markowitz et al., 1955), is likely upregulated in response to IOP elevation, but the significance of this for glaucoma is not clear.

Mu¨ller glia and heat shock proteins

Heat shock proteins (Hsps) are upregulated in glaucoma (Park et al., 2001; Sakai et al., 2003; Tezel et al., 2004; Qing et al., 2005). For example, HSP27, particularly an activated, phosphorylated form, is upregulated in Mu¨ller glia cells in human glaucoma (Tezel et al., 2000), a rat model of glaucoma (Park et al., 2001), and more recently, DBA/2J glaucoma (Huang et al., 2007). HSP27 is a low-molecular-weight heat shock protein shown to have protective properties in response to