Synaptopathy in cone and rod cells after retinal detachment and reattachment

Using the powerful technique of stimulated emission depletion (STED) confocal microscopy in combination with 3D imaging, we describe the degeneration of cone and rod synapses after one week of retinal detachment in a porcine model. Synaptic invaginations are lost, ribbons change size and shape, and bipolar dendrites sprout. Spontaneous reattachment after hours up to 2 days after detachment appears to restore cone pedicles but does not repair rod spherules one week later. Disjunction of rod synapses remains, both at the point of initial detachment and in areas that were not detached. Moreover, electroretinographic recording of photopic and scotopic b-waves and the flicker response demonstrate that synaptic function of both cone and rod cells remains impaired, even though a-wave function has returned to baseline. The beneficial effects of subretinal injection of the Rho kinase (ROCK) inhibitor AR13503 at the time of detachment, previously shown to reduce injury 2 days after detachment, are now shown to remain for one week. Structural and functional synaptic degeneration is significantly reduced for both cone and rod photoreceptors with ROCK inhibition. The persistence of synaptic injury after these relatively small detachments that is followed by rapid reattachment indicates the vulnerability of photoreceptor synapses to injury, in part due to increased Rho signaling. Further, the data suggest that visual dysfunction seen in patients after detachment and otherwise successful reattachment can be a result of synaptopathy. Finally, the results reinforce the potential for ROCK inhibition to reduce injury due to iatrogenic detachment in procedures such as gene therapy.