Zinc has been shown to have multiple important and distinct effects on synaptic transmission and has been implicated as a critical mediator of neuronal injury. We have now discovered a previously unrecognized role for zinc as a major suppressor of axon regeneration and cell survival following axonal injury in the central nervous system (CNS). Under normal conditions, neurons in the adult CNS cannot regenerate damaged axons, placing severe limitations on the amount of recovery that can occur after spinal cord injury, stroke, and other types of neurological damage. The optic nerve is an integral part of the central nervous system (CNS) that has been widely used to investigate CNS regeneration due to its accessibility, anatomical simplicity, and functional importance. Although the projection neurons of the eye, the retinal ganglion cells (RGCs), are normally unable to regenerate injured axons, this inability can be partially reversed in mice by treatments that activate RGCs' intrinsic growth state and by counteracting cell-extrinsic inhibitors of axon growth. However, these manipulations result in only limited regeneration, suggesting that our current understanding of the factors that regulate neurons' regenerative potential in the CNS is incomplete. Our preliminary data show that within 6 hours after injuring the optic nerve, there is a dramatic elevation of Zn2+ in the inner plexiform layer (IPL) of the retina, which contains synaptic contacts from amacrine and bipolar cells onto the dendrites of RGCs. This increase represents a very early event following optic nerve damage. Over the next few days, Zn2+ accumulates in RGC somata. Importantly, agents that chelate extracellular Zn2+ provide enduring protection against RGC death and have a dramatic effect on these cells' ability to regenerate injured axons through the optic nerve. We therefore hypothesize that Zn2+ is a major suppressor of the regenerative potential of axons after nerve injury as well as a cause of neuronal death.
The specific aims are to: 1) Characterize the timing, localization, and mechanism of Zn2+ accumulation following optic nerve crush; 2) Determine whether Zn2+ regulates axon regeneration via histone deacetylases; and 3) Characterize the pathways by which Zn2+ suppresses, and chelation enhances, RGC survival. These studies will add greatly to our understanding of the role that Zn2+ plays in the normal and injured nervous system, and may lead to treatments to help improve outcome after CNS injury.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY024481-03
Application #
9189615
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Liberman, Ellen S
Project Start
2014-12-02
Project End
2019-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Marin, Miguel A; de Lima, Silmara; Gilbert, Hui-Ya et al. (2016) Reassembly of Excitable Domains after CNS Axon Regeneration. J Neurosci 36:9148-60