Influence of Opa1 Mutation on Survival and Function of Retinal Ganglion Cells.

PURPOSE

Mutations in the OPA1 gene cause autosomal dominant optic atrophy (ADOA), a visual disorder associated with degeneration of retinal ganglion cells (RGCs). Here, we characterized the disease progression in a homologous mouse model B6;C3-Opa1 329-355del and asked whether the pronounced cell death affects certain RGC types more than others.

METHODS

The influence of the Opa1 mutation was assessed by morphologic (retina and optic nerve histology) and functional (multielectrode array) methods.

RESULTS

The RGC loss of approximately 50% within 18 months was significantly more pronounced in RGCs with small-caliber axons. Small-caliber axon RGCs comprise a variety of functional RGC types. Accordingly, electrophysiological analyses of RGCs did not show a dropout of distinct functional RGC subgroups. However, the response properties of RGCs were affected significantly by the mutation. Surprisingly, these functional changes were different under different luminance conditions (scotopic, mesopic, and photopic). Finally, melanopsin cells are known to be less susceptible to retinal insults. We found that these cells are also spared in the Opa1 mouse model, and demonstrated for the first time that this resistance persisted even when the melanopsin gene had been knocked-out.

CONCLUSIONS

Small-caliber axons show a higher vulnerability to the Opa1 mutation in our mouse model for ADOA. Luminance-dependent functional changes suggest an influence of the Opa1 mutation on the retinal circuitry upstream of RGCs. Photoresponsive RGCs are protected against cell death due to the Opa1 mutation, but not by melanopsin expression itself.