Larry I. Benowitz,
Harvard Medical School, USA.
Title: Optic nerve regeneration: regulation by amacrine cells, nitric oxide, and zinc
Biography
Biography: Larry I. Benowitz,
Abstract
Retinal Ganglion Cells (RGCs), the neurons that project visual information from the eye to the brain, cannot regenerate their axons once the optic nerve has been injured and soon begin to die. This failure has dire consequences for victims of traumatic or ischemic nerve damage or degenerative diseases such as glaucoma. Our lab and others have recently identified methods that enable some RGCs to regenerate axons from the eye to the brain, yet most RGCs go on to die and only a small fraction of surviving RGCs regenerate their axons. These findings imply the existence of other major suppressors of RGC survival and axon regeneration. We recently identified mobile zinc (Zn2+) one such factor. Within an hour after optic
nerve injury, Zn2+ increases dramatically in synaptic vesicles of amacrine cells (ACs), the inhibitory interneurons of the retina, then transfers slowly to injured RGCs. Zn2+ chelation leads to the persistent survival of many RGCs and to appreciable axon regeneration, with a therapeutic window of several days. New results show that Zn2+ elevation is induced by nitric oxide (NO), a gaseous signal that is generated in a small population of ACs via glutamate-dependent activation of the enzyme NO synthase-1 (NOS1). A novel fl uorescent NO sensor reveals that retinal NO levels increase within 30 minutes of optic nerve damage. NO or a derivative thereof probably liberates Zn2+ from proteins such as metallothioneins via nitrosylation of Zn2+- binding cysteine residues. Surprisingly, we also find that NO has a second, positive effect on optic nerve regeneration through a cGMP-dependent pathway. Besides eliminating Zn2+ accumulation in the retina, AC-specific deletion of NOS1 blocked the regeneration that would otherwise have occurred upon Zn2+ chelation. Conversely, elevation of NO with the NO donor DETANONOate or prevention of cGMP degradation was sufficient to induce axon regeneration. Thus, NO generated by NOS1 in a small population of ACs is responsible for the deleterious elevation of Zn2+ after optic nerve regeneration, but also exerts a positive effect on optic nerve regeneration via cGMP signaling.