Migration of mononuclear phagocytes into the subretina contributes to retinal degeneration in the Leber congenital amaurosis RPE65/rd12 mouse model

Abstract

Purpose : To assess the role of Mononuclear Phagocytes (MP) in retinal degeneration in the RPE65/rd12 mouse model

Methods : Thirty-nine RPE65/rd12 and ten C57BL/6J wild-type mice were used. RPE65/rd12 mice were treated with minocycline by daily intraperitoneal injection (50 mg/kg) for 8 weeks starting at age post-natal day 28 (p28). MP density in the sub-retina was determined by choroid-RPE flat-mount analysis and retinal function was determined by electroretinogram (ERG).

Results : MPs in the C57BL/6J retinas at p28 and p84 were exclusively located in the inner retinal layers. In RPE65/rd12 retinas, MPs migrated into the sub-retina as early as p56. By p84 the density of MPs in the sub-retina increased by nearly 3-fold. MP density in the central retina was higher by 2 fold compared with the peripheral retina. Minocycline treatment reduced MP density in the peripheral sub-retina by 59% (16.2±1.8 cell/mm² vs. 27.2±2.4 cell/mm², p<0.01). Maximal ERG b-wave responses were significantly higher in minocycline- vs. placebo- treated mice under light adaptation conditions following 8 weeks of treatment (mean ± SE: 199µv ± 28µv vs. 129.8µv ±9.8µv, p=0.016).

Conclusions : MP migration into the subretina contributes to retinal degeneration in RPE65/rd12 mice. These results may provide a rationale for developing treatments that target MP migration for treating LCA and possibly other RP forms associated with retinoid cycle defects.

This is a 2020 ARVO Annual Meeting abstract.