Neurotrophic deficiency preconditioning improves the natural history of disease in DBA/2J glaucoma

Abstract

Purpose : In mice, lesion to the superior colliculus (SC) of one side induces chronic deficiency of target-derived trophic support to the contralateral eye associated with overexpression of endogenous retinal BDNF and TrkB but not cell death (Yang et al, IOVS 2013). We investigated whether target-derived neurotrophic deficiency preconditioning alters the natural history of disease in DBA/2J glaucoma.

Methods : DBA/2J (D2) (n=11) and C57BL/6J (B6) (n=14) mice received a lesion of the right SC (rSCL) at 3 months of age and were longitudinally monitored with pattern electroretinogram (PERG) over one year. At endpoint, retinal ganglion cell (RGC) density was assessed in flat-mounted retinas.

Results : In rSCL-B6 mice, the PERG of the left eye dropped to about 50% of the baseline amplitude two weeks after rSCL, but partially recovered to ~75% of baseline amplitude after one month and remained stable thereafter. The PERG of the right eye did not significantly change over the follow-up period (Two-way ANOVA: Eye, P<0.0001; age x eye, P=0.0003). Expression of retinal BDNF and TrkB in the left eye increased by ~ 3 fold one month after rSCL. At endpoint, RGC density was similar in the two eyes. In rSCL-D2 mice, IOP progressively increased with age symmetrically in both eyes until 9 months and then decreased. The PERG of the right eye progressively declined over 11 months as previously reported for unlesioned D2 mice (Saleh et al, IOVS, 2007). The PERG of the left eye displayed a steeper amplitude drop two weeks after rSCL compared to the right eye (OS/OD = 0.7) but progressively recovered and surpassed that of the right eye until to reach an OS/OD amplitude ratio of 1.4 at 9-11 months (Two-way ANOVA, age, P<0.001, Eye, P=0.03). PERG latency also became shorter in OS by 10 ms compared to OD (Two-way ANOVA: Eye, P=0.015). At endpoint, the mean RGC density was significantly higher in OS (255 RGC/mm²) compared to OD (139 RGC/mm²), P<0.01.

Conclusions : Neurotrophic deficiency preconditioning is neuroprotective in DBA/2J glaucoma. This represents a proof of concept that there is a stage of neurotrophic-dependent RGC plasticity in the initial stages of glaucoma that may represent a rationale and a target for treatment.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.