Changes in retinal neuronal connectivity in a mouse model of dominant optic atrophy

Abstract

AbstractPurpose The heterozygous mutation, B6;C3‐Opa1Q285STOP which models autosomal dominant optic atrophy results in a 50% reduction in Opa1 transcript and protein in the mouse retina and neural tissues and is associated with visual dysfunction mirroring that found in human patients. We have previously reported retinal ganglion cell dendropathy in the absence of cell loss in this model. This study aims to explore the mechanisms that underlie this retinal ganglion cell dendropathy.Methods Changes in retinal ganglion cell connectivity were explored in Opa1+/‐ mutant mice (n = 27) and accompanying age and sex matched controls (wt; n = 27) at 3 time points (12, 14 and 15 months of age) by immunohistochemistry, western blot analysis, TUNEL labelling and electron microscopy.Results We report RGC dysfunction and changes in RGC connectivity in the absence of soma loss or microglial activation. We observed a dramatic decrease in PSD‐95 levels across all ages in the Opa1+/‐ mice suggesting synaptic atrophy coupled with a selective degeneration of glutamatergic but not GABA‐ergic synaptic sites. There was an increase in synaptic vesicle distribution assessed by immunohistochemistry, western blot and electron microscopy. γ‐synuclein labelling confirmed stable RGC populations without significant evidence of apoptosis on TUNEL staining.Conclusion In conclusion; we show discrete changes in RGC connectivity localised to sublamina b. These results highlight the importance of normal mitochondrial fusion balance as influenced by the OPA1 protein in maintaining neural cell connectivity. Changes in connectivity precede the onset of clinical visual loss and structural changes in optic nerve in the absence of significant apoptosis or microglial upregulation.