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Editors Selection IGR 9-4

Basic Research: Ultrastructural anatomy of the rat ONH

Comment by Robert Nickells on:

47722 Structural basis of glaucoma: The fortified astrocytes of the optic nerve head are the target of raised intraocular pressure, Dai C; Khaw PT; Yin ZQ et al., GLIA, 2012; 60: 13-28

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It is widely accepted that the earliest site of glaucomatous damage to ganglion cells is to the axons passing through the lamina cribrosa (LC). In primates, the LC is comprised of large beams of connective tissue, suggesting that these structures are able to transduce IOP-induced strain on the optic nerve head (ONH) to either the astrocytes that populate the region, or the axons that pass through it. Nearly identical pathology occurs in rodent models of glaucoma, yet these animals have anatomically distinct laminar regions. Instead, the lamina is comprised of axons, which pass through a field of astrocytes. ^1,2 Dai et al. (1684) present a beautiful ultrastructural study of the anatomy of the rat ONH, both in normotensive eyes and in the Morrison model of glaucoma.⁴ At this site, the astrocytes have extensive ventral (inferior) attachments to the wall of the optic nerve sheath, and they then radiate processes across the canal making intricate finger-like interdigitations with the dorsal (superior) wall of the canal. Additionally, the cytoplasm of these astrocytes may contain a greater concentration of cytoskeletal filaments, which transverse the cell in a plane perpendicular to the orientation of the axons passing through this region. Because of this appearance, the authors call these 'fortified' astrocytes, and suggest that they may act like the connective tissue beams present in the primate ONH. Under increased IOP, these cells lose contacts with the dorsal scleral wall, resulting in the formation of large bleblike spaces between the astrocyte terminals and the sheath of the ONH. This pathology corresponds to the region of earliest axon loss in this model.

Like many ultrastructure studies, the data is open to interpretation. Dai et al. interpret that the strain placed across the scleral canal causes the astrocytes to physically tear away from their dorsal connections. Although this may be true, the force is likely less than sufficient to cause this, and the retraction of the processes may be more of an active cellular phenomenon. Possibly a more intriguing speculation from the authors, however, is the idea that loss of astrocyte:axon contacts leads to a loss of metabolic support for the axons in this region. An important function of astrocytes is to provide lactate to neurons, especially in times of metabolic stress. Loss of such support, especially to non-myelinated axons trying to transport materials across an increasing translaminar pressure gradient⁵ may ultimately be the critical link between elevated IOP and ganglion cell damage.

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