Astrocytes

Named for their stellate shape (Fig. 1.18A), astrocytes are confined almost exclusively to the innermost retinal layers. Using Golgi-impregnated whole mounts of retinas from human, baboon, and monkey, Ogden (1978) described two morphologically different forms of astrocyte, both with densely stained, compact, oval perikarya located in the nerve fiber layer. One type appeared elongated and had processes that parallelled the course of the nerve fibers without making specialized vascular contacts. The other type was the classic star-shaped variety, with shorter processes that traversed the nerve fiber bundles to make vascular attachments. In the electron microscope (Fig. 1.18B), these processes can be seen enveloping the blood vessels with apparently no perivascular space between the adventitia of the vessel wall and the glial cells (Hogan and Feeney, 1963; Hogan et al., 1971).

More definitive studies, particularly with respect to the development, organization, and distribution of retinal astrocytes, have since been performed with immunocytochemistry using antibodies against GFAP, a major constituent of astrocytic intermediate filaments (Bigmami et al., 1972). Under normal circumstances neither microglia nor mammalian Müller cells contain significant amounts of GFAP. Thus, GFAP immunoreactivity provides a reliable marker for the identification and localization of astrocytes in

Figure 1.18. A. Light micrograph of GFAP-positive astrocytes in a whole-mount preparation from the peripheral retina of cat. Bar = 100 ^m (Karschin etal., 1986). (Copyright 1986 Wiley-Liss, Inc., a division of John Wiley & Sons, Inc., reprinted with permission.) B. Electron micrograph showing the processes of an astrocyte (a) contacting the wall of a capillary (c) (magnification 12,000) (Hogan et al., 1971). (Copyright 1971 W.B. Saunders, reprinted with permission.)

Figure 1.18. A. Light micrograph of GFAP-positive astrocytes in a whole-mount preparation from the peripheral retina of cat. Bar = 100 ^m (Karschin etal., 1986). (Copyright 1986 Wiley-Liss, Inc., a division of John Wiley & Sons, Inc., reprinted with permission.) B. Electron micrograph showing the processes of an astrocyte (a) contacting the wall of a capillary (c) (magnification 12,000) (Hogan et al., 1971). (Copyright 1971 W.B. Saunders, reprinted with permission.)

Figure 1.19. The relation of astrocytes to the vasculature and nerve fibers in cat retina. A. Astrocytic processes in the region of the optic disc extend processes that cross, but do not seem to contact, blood vessels. B. Processes of GFAP-labeled astrocytes form thick bundles that are aligned in parallel with the ganglion cell axons ofthe nerve fiber layer (Karschin etal., 1986). (Copyright 1986 Wiley-Liss, Inc., a division of John Wiley & Sons, Inc., reprinted with permission.)

Figure 1.19. The relation of astrocytes to the vasculature and nerve fibers in cat retina. A. Astrocytic processes in the region of the optic disc extend processes that cross, but do not seem to contact, blood vessels. B. Processes of GFAP-labeled astrocytes form thick bundles that are aligned in parallel with the ganglion cell axons ofthe nerve fiber layer (Karschin etal., 1986). (Copyright 1986 Wiley-Liss, Inc., a division of John Wiley & Sons, Inc., reprinted with permission.)

mammalian retina. Using this method it has been possible to trace the development of retinal astrocytes, and to demonstrate their close association with the ganglion cell axons and vasculature (Fig. 1.19) of the nerve fiber layer of the retina (Karschin et al., 1986; Stone and Dreher, 1987; Schnitzer 1987b).

In the partially vascularized rabbit retina, for example, astrocytes are located in the band of medullary rays, a horizontally elongated group of myelinated axons of ganglion cells that also defines the extent of the vascular area (Stone and Dreher, 1987, Schnitzer, 1987a; Tout et al., 1988). In the retinas of horse (Schnitzer, 1987b; Schnitzer, 1988a) and opossum (Stone and Dreher, 1987), which are almost completely devoid of retinal vessels, the vasculature is confined to the region of the optic disc and the immediately adjacent surrounding area; this is the only region containing astrocytes. Since in these species, as well as in rabbit, ganglion cell axons devoid of astrocytes are present throughout the retina, the findings tend to support the contention that retinal astrocytes relate closely to the presence of intraretinal vessels (Schnitzer, 1987b, 1988b). Evidence that retinal astrocytes differentiate in the optic nerve close to the eye and migrate into the retina later in development (Ling and Stone, 1988; Watanabe and Raff, 1988; Ling et al., 1989; Chan-Ling and Stone, 1991; Sarthy and Fu, 1990), suggests that they may in fact enter the retina with its vasculature (Stone and Dreher, 1987).

Their numbers and distribution, on the other hand, appear to be influenced by the density of nerve fibers, which they invest. In the fully vas-cularized retina of the cat, for example, astrocytes are distributed throughout the inner retina in a pattern that mirrors closely that of the axon bundles (Karschin et al., 1986; Stone and Dreher, 1987). Moreover, reducing the number of viable ganglion cell axons by photocoagulation results in a reduction in the number of astrocytes within the lesioned area (Karschin et al., 1986). But despite this intimate relationship (Bussow, 1980), the structural development of explanted murine retina is apparently independent of the presence of astrocytes, i.e., explants that lack astrocytes grow, differentiate, and acquire the same neuronal structure as do retina well populated with astrocytes (Huxlin et al., 1992). Relatively little is known of the functional relations between astroglia and the nerve fibers and blood vessels with which they are associated. Because astrocytes are known to produce vascular endothelial growth factor (VEGF), they may be involved in the development of the retinal vasculature (Stone et al., 1995a).

Recently, confocal microscopy and computer-assisted image reconstruction of astrocytes in the vascularized retina of pigs, rats, and cats have provided striking three-dimensional views of astroglial ensheathment of the retinal vessels and their association with ganglion cell axons (Rungger-Brindle et al., 1993). Differences were evident in the disposition of astro-cytes among the various species, but a number of general features emerged. Reconstructed images from retinas double-stained for GFAP (astrocytes) and for a-smooth muscle actin or collagen IV (blood vessels) enabled visualization of the asymmetric astrocytic ensheathment of blood vessels. Most notable was the preponderance of GFAP-positive fibers clustering on the vitreal and lateral sides of the blood vessels in close apposition to the vitreal surface of the retina. In addition, this type of confocal imagery enabled the authors to detect individual astrocytes that extended fibers to insert into axonal bundles, while other of its fibers simultaneously contacted the blood vessel wall; in some instances, astrocytic processes extended to the vitreo-retinal surface. The authors hypothesized that these elements function as communication links between ganglion cell axons, the retinal vasculature, and the vitreous body (Rungger-Brandle et al., 1993). Although the means

of communication and the nature of this interaction have yet to be firmly established, the suggestion that this arrangement may provide a system for the regulation of extracellular potassium (spatial buffering) in the inner retina is not without merit. The channel properties of retinal astrocytes (Newman, 1986; Clark and Mobbs, 1992), the communicating (gap) junctions they make with other astrocytes (Marc et al., 1988; Burns and Tyler, 1990; Robinson et al., 1993; Ramirez et al., 1996), and evidence that both the vitreous and blood vessels can serve as a "sink" for K+ (Newman et al., 1984; Newman, 1986) are consistent with this view.

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