number (%)

No NMDA, 1 mMMg2+

9 ± 4

NMDA, 1 mM Mg2+

28 ± 7

NMDA, 10 mMMg2+

8 ± 4

NMDA, low Na+

23 ± 3

NMDA, low Ca2+

6 ± 6

Figure. 6.13. Effect ofNMDA on retinal glial cell proliferation. A. Dose-response curve for NMDA effect on proliferation. B. Effect of extracellular concentrations of magnesium, sodium, and calcium on the NMDA-induced proliferation of human retinal glial cells in culture. While sodium removal had minimal effect on proliferation, low Ca2+ prevented NMDA-induced proliferation (Uchihori and Puro, 1993b). (Copyright 1993 Elsevier Science, reprinted with permission.)

undergo mitotic activity in an appropriate environment. It is possible that as the retina matures, either the supply of endogenous mitogens becomes limiting or that mitogen-receptors are down-regulated in Müller cells. Under pathological conditions, the availability of mitotic agents and the expression of their receptors are probably responsible for initiating mitotic activity. The inherent capacity of Müller cells to divide makes them excellent candidates as mediators of ocular pathology in conditions such as massive retinal gliosis (Nork et al., 1986; Rodrigues et al., 1987), retinal tumors (Jakobiec et al., 1983; Craft et al., 1985), and proliferative diabetic retinopathy (Nork et al., 1987).

6.5.7. Molecular Changes

The cytological changes observed in Müller cells in response to injury are accompanied by significant alterations in gene expression. Whereas proteins such as GFAP, Glutamate/aspartate transporter (GLAST) , CNTF, and target of the antiproliferative antibody (TAPA) are upregulated under pathological conditions, other proteins appear to be down-regulated (Table 6.3) (Sagaretal., 1991; Chenetal., 1994; Grosche etal., 1995;Yoshidaetal., 1995; Otori et al., 1995; Wen et al., 1995; Clarke and Geisert, 1998; Lewis et al., 1989; Sarthy, 1982). The significance of these changes and the underlying gene regulatory mechanisms, however, remain to be elucidated.

A prominent feature of reactive gliosis is that the Müller cell cytoplasm becomes crowded with organelles and filaments (Fig. 6.8). In particular,

Table 6.3. Proteins Highly Expressed or Induced in Müller Cells

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