Here, we use a mouse model (DBA/2J) to readdress the location of insult(s) to retinal ganglion cells (RGCs) in glaucoma. We localize an early sign of axon damage to an astrocyte-rich region of the optic nerve just posterior to the retina, analogous to the lamina cribrosa. In this region, a network of astrocytes associates intimately with RGC axons. Using BAX-deficient DBA/2J mice, which retain all of their RGCs, we provide experimental evidence for an insult within or very close to the lamina in the optic nerve. We show that proximal axon segments attached to their cell bodies survive to the proximity of the lamina. In contrast, axon segments in the lamina and behind the eye degenerate. Finally, the Wlds allele, which is known to protect against insults to axons, strongly protects against DBA/2J glaucoma and preserves RGC activity as measured by pattern electroretinography. These experiments provide strong evidence for a local insult to axons in the optic nerve.

Neurons seem to have at least two self-destruct programs. Like other cell types, they have an intracellular death program for undergoing apoptosis when they are injured, infected, or not needed. In addition, they apparently have a second, molecularly distinct self-destruct program in their axon. This program is activated when the axon is severed and leads to the rapid degeneration of the isolated part of the cut axon. Do neurons also use this second program to prune their axonal tree during development and to conserve resources in response to chronic insults?

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