MAR 15, 2018 9:00 AM PDT

Axon Regeneration in the CNS: Insights from the Optic Nerve

Presented at: Neuroscience 2018
Speaker
  • Professor of Neurosurgery and Ophthalmology, Harvard Medical School, Neurosurgical Innovation and Research Endowed Professor, Boston Children's Hospital
    BIOGRAPHY

Abstract

The inability of neurons to regenerate damaged axons within the CNS has dire consequences for victims of traumatic or ischemic brain injury and multiple neurodegenerative diseases. Like other CNS pathways, the optic nerve cannot regenerate if injured and soon the retinal ganglion cells (RGCs), the projection neurons of the eye, begin to die, precluding visual recovery. Our lab and others have identified methods that enable some RGCs to regenerate axons from the eye to the brain. Some of these methods include controlled intraocular inflammation and elevation of on-comodulin and other growth factors, deletion of genes that suppress regeneration such as pten, socs3, klf4 and -9, and counteracting cell-extrinsic suppressors of axon growth by deleting re-ceptors for Nogo and other molecules{Benowitz, 2017 #5372}. Nonetheless, even under the best of circumstances, most RGCs go on to die and only a small fraction of the surviving RGCs re-generate their axons {de Lima, 2012 #4249}. 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, and is then exocytosed and accumulates in injured RGCs. Zn2+ chelation leads to the persistent survival of many RGCs and to appreciable axon regeneration, with a therapeutic window of several days{Li, 2017 #5363}. Zn2+ elevation is induced by nitric oxide (NO), a gaseous signal that is generated in a small population of ACs by the enzyme NO synthase-1 (NOS1). A novel fluorescent NO sensor reveal a dramatic increase in retinal NO levels within an hour of optic nerve damage. NO or a derivative is likely to liberate Zn2+ from metallothioneins. NO also has a second, positive effect on optic nerve regeneration through a cGMP-dependent pathway. 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 sig-naling. These findings, together with others in the field, are bringing us closer to improving out-come after injury to the optic nerve and are likely to have relevance to parts of the CNS.


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MAR 15, 2018 9:00 AM PDT

Axon Regeneration in the CNS: Insights from the Optic Nerve

Presented at: Neuroscience 2018


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