The Effect of Advancing Age and Intraocular Pressure Injury on Retinal Ganglion Cell Function and Synaptic Connectivity

Age and elevated intraocular pressure (IOP) are the two major risk factors for developing glaucoma, a leading cause of blindness worldwide that is characterized by the loss of retinal ganglion cells (RGCs). Although vision loss is irreversible over the long term, accumulating evidence points to short-term improvement of vision in glaucoma patients in response to certain interventions, suggesting that RGCs have the capacity to recover function. In the present study, we sought to investigate the mechanisms underlying loss and recovery of RGC function in response to aging and IOP injury, with a focus on synaptic connectivity. Using electroretinography, we found that advancing age was associated with a substantial reduction in function across all retinal layers in the absence of significant cell loss. A superimposed injury induced by IOP elevation led to the selective loss of RGC function in young and middle-aged mice that was associated with a decrease in paired excitatory synapses. RGC functional recovery after injury was significantly delayed in middle-aged mice and was mediated through different cellular mechanisms than in young mice. Whereas young mice regained excitatory synaptic inputs from bipolar cells, functional recovery in older mice was instead mediated through an increase in intrinsic RGC excitability, associated with modulation of the action potential threshold and axon initial segment length. Our findings provide new insights into the impact of advancing age on RGC resilience to IOP injury. Boosting the capacity for RGC recovery by reversing the effect of advancing age offers a new therapeutic approach for glaucoma management.