Zinc is a critical regulator of cell death and axon regeneration after CNS injury
Zinc has been shown to have multiple important and distinct effects on synaptic transmission and hasbeen implicated as a critical mediator of neuronal injury. We have now discovered a previously unrecognizedrole for zinc as a major suppressor of axon regeneration and cell survival following axonal injuryin the central nervous system (CNS). Under normal conditions, neurons in the adult CNS cannotregenerate damaged axons, placing severe limitations on the amount of recovery that can occur afterspinal cord injury, stroke, and other types of neurological damage. The optic nerve is an integral part ofthe central nervous system (CNS) that has been widely used to investigate CNS regeneration due to itsaccessibility, anatomical simplicity, and functional importance. Although the projection neurons of theeye, the retinal ganglion cells (RGCs), are normally unable to regenerate injured axons, this inabilitycan be partially reversed in mice by treatments that activate RGCs’ intrinsic growth state and by counteractingcell-extrinsic inhibitors of axon growth. However, these manipulations result in only limited regeneration,suggesting that our current understanding of the factors that regulate neurons’ regenerativepotential in the CNS is incomplete. Our preliminary data show that within 6 hours after injuring the opticnerve, there is a dramatic elevation of Zn2+ in the inner plexiform layer (IPL) of the retina, which containssynaptic contacts from amacrine and bipolar cells onto the dendrites of RGCs. This increase representsa very early event following optic nerve damage. Over the next few days, Zn2+ accumulates inRGC somata. Importantly, agents that chelate extracellular Zn2+ provide enduring protection againstRGC death and have a dramatic effect on these cells’ ability to regenerate injured axons through theoptic nerve. We therefore hypothesize that Zn2+ is a major suppressor of the regenerative potential ofaxons 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.