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Y. Duan, W. Kong, M. Benny Klimek, J. L. Goldberg; Loss of Retinal Ganglion Cell Trophic Responsiveness Is Correlated With Reduced Electrical Activity. Invest. Ophthalmol. Vis. Sci. 2009;50(13):127.
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Why do neurons in the mature central nervous system (CNS) die after injury? Recent evidence suggests that retinal ganglion cells (RGCs) die after axon injury for two reasons: they are cut off from target-derived trophic signals, and they lose responsiveness to such signals. Interestingly, exogenous trophic support weakly promotes RGC survival after axotomy, but trophic responsiveness can be enhanced by electrical activity or by elevating cyclic AMP (cAMP). This raises the hypothesis that RGCs fail to respond to endogenous or exogenous trophic signals after injury because they are less electrically active, fail to elevate levels of cAMP, or both. Here, we directly measure trophic responsiveness and electrical activity in RGCs after optic nerve injury.
The time course of RGCs survival after axotomy in postnatal rats were first characterized by quantifying the total number of cholera toxin B conjugated to Alexa 488 positive cells after retrograde labeling. The electrical activity of RGCs after axotomy was measured by calcium imaging of endogenous retinal waves in the postnatal rat retina. The trophic responsiveness of RGCs was assessed by measuring the Brn3a positive RGCs’ ability to activate MAP Kinase (P-MAPK).
We found that in the normal retina, the P-MAPK translocation to RGC nuclei can be activated by exogenous BDNF alone. By 16 hours after axotomy, trophic responsiveness decreased significantly. Furthermore, we found that retinal waves continue at a slower frequency and with lower amplitude starting 16 hours after axotomy. This decrease persisted at 40 hours, when 90% of the RGCs had undergone apoptosis. Elevation of cAMP increased wave frequency but not wave amplitude.
Thus, after optic nerve injury, overall electrical activity in RGCs decreases in a time dependent manner, which correlates with the loss of their responsiveness to trophic factors. These experiments may point to an explanation for the failure of RGC survival after injury, and ultimately to new therapeutic strategies.
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