Long-Term Evaluation Of Visual Functional Changes In Rotenone Induced Rat Model Of Leber’s Hereditary Optic Neuropathy

Abstract

Purpose: : To evaluate changes in the optic nerve fiber layer (NFL) thickness and visual function following rotenone microsphere administration into the rat superior colliculus (SC) and to establish this as a suitable model for studying long-term effects of therapeutic interventions for Leber’s hereditary optic neuropathy (LHON).

Methods: : Rotenone-loaded microspheres (3 μl) were injected into the optical layer of the SC of Long Evans (LE) rats. Retinal NFL thickness was determined using optical coherence tomography (OCT). Visual function was evaluated based on optokinetic head-tracking response and SC electrophysiology. OCT and optokinetic head-tracking assessments were performed every 2 weeks post-injection. Baseline measurements were assessed prior to the injection of rotenone. At 10 weeks post-injection, responses to varying light intensities (0.90 to -2.31 log cd/m²) were recorded from multiple sites over the surface of the SC. Age-matched, non-injected LE rats were used as the control group.

Results: : OCT analysis showed substantial loss (up to 42.6%) of NFL thickness through 3 weeks post-injection. The above degree of NFL thickness loss was maintained throughout the study period (10 weeks post-injection). Optokinetic response in rotenone treated rats also showed a corresponding decrease (up to 26.0%). Differences between the rotenone treated and non-treated animals were also observed in the properties of the light-evoked SC responses. At low level light stimulation (-2.31 log cd/m²) the rotenone injected rats manifested longer response onset latencies (67.12 ± 1.46 ms) compared to the control (non-injected) group (47.03 ± 0.58 ms). Peak response amplitude was considerably decreased in the rotenone injected rats (98.92 ± 7.89 µV) compared to the non-treated group (203.36 ± 18.95 µV).

Conclusions: : Administration of rotenone microspheres to the SC lead to a loss of NFL thickness as well as behavioral and electrophysiological defects that persisted up to 10 weeks post-injection. These data suggest that rotenone treated rat serves as a suitable model for long-term evaluation of therapeutic strategies for LHON.

Keywords: visual impairment: neuro-ophthalmological disease • ganglion cells • electrophysiology: non-clinical