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Aurora Maria Fontainhas, Ellen Townes-Anderson; RhoA Inactivation Prevents Photoreceptor Axon Retraction in an In Vitro Model of Acute Retinal Detachment. Invest. Ophthalmol. Vis. Sci. 2011;52(1):579-587. doi: 10.1167/iovs.10-5744.
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An early injury response to retinal detachment is disruption of synaptic connectivity between photoreceptors and second-order neurons. Most dramatic is the retraction of rod cell axons and their terminals away from the outer synaptic layer and toward their cell bodies. This study tested whether axonal retraction in detached retina was due to the activation of the small GTPase RhoA and was preventable using RhoA antagonists.
Retinal detachments were created in in vitro preparations of porcine eyecups. RhoA activation was determined with a Rhotekin binding assay. To block axon retraction, drugs were applied to neural retinal explants either before or after detachment from the retinal pigment epithelium. Presynaptic movement was quantified by image analysis of double-labeled retinas examined with confocal microscopy.
Active RhoA increases transiently after detachment followed by morphologic evidence of axonal retraction over the next 24 hours. Pretreating the retina with a RhoA antagonist, CT-04, or a Rho kinase inhibitor, Y27632, at multiple concentrations significantly inhibited axonal retraction. Reducing calcium influx through L-type calcium channels with nicardipine also blocked retraction. To create a more plausible therapeutic scenario, drug treatments were delayed and applied after retinal detachment. The Rho kinase inhibitor, but not nicardipine, significantly blocked rod axonal retraction when applied up to 6 hours after detachment.
Thus, RhoA and downstream Rho kinase activity constitute part of the mechanism that produces rod axonal retraction in retinal explants. Treatments that manipulate RhoA signaling may promote synaptic stability after retinal detachment.
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