Foveal RGCs develop altered calcium dynamics weeks after photoreceptor ablation

Abstract

Vision restoration therapies aim to restore light sensitivity to the retina following photoreceptor (PR) degeneration. Physiological changes in retinal ganglion cells (RGCs) have been reported in rodent models of PR loss but this has not been investigated in primates. By expressing both a calcium indicator (GCaMP6s) and an optogenetic actuator (ChrimsonR) in foveal RGCs of a macaque, we reactivate RGCs in vivo and assess activity in the weeks and years following PR loss. Cones were ablated with an ultrafast laser delivered through an adaptive optics scanning light ophthalmoscope (AOSLO). A 0.5 s, 25Hz stimulus was delivered to optogenetically stimulate the deafferented RGCs, and the resulting GCaMP fluorescence rise and decay were recorded from RGCs with an AOSLO. These measurements were repeated in the 10 weeks immediately after photoreceptor ablation and at 2 years. The mean time to peak calcium was stable in deafferented RGCs over the 10 weeks post ablation (paired t-test, p<0.001), while the mean decay constant of the calcium response decreased 2.1 fold (2.5±0.5 s to 1.2±0.2 s SD) within 8 weeks. The presence of optogenetic responses 2 years after PR loss and the stable rise time is promising for vision restoration therapies. However, the 2-fold reduction in the decay constant of the calcium response indicates that abnormal dynamics develop in the inner retina weeks after PR loss. Whether this phenomenon is pathological or protective is currently unknown.