Abstract
Purpose:
The development of glaucoma is associated with activation of the complement cascade and the marked accumulation complement components 1q (C1q) and 3 (C3) in association with retinal ganglion cells (RGC). In order to determine the functional significance of C1q and C3 in the pathophysiology of glaucoma, we evaluated retinal ganglion cell (RGC) and axonal loss in B6-Sh3pxd2 nee (nee) mice with and without targeted deletions in either the C1qa or C3 genes.
Methods:
Nee mice were bred either with those containing targeted deletions in C1q or C3 to create double knockouts. At 8 weeks of age the intraocular pressure (IOP) was determined using a rebound tonometer. The animals were then euthanized and the eyes and optic nerves were harvested. The number of surviving gamma synuclein immunoreactive RGC was determined in flat mounted preparations of retina and axonal damage in the optic nerve was evaluated using a 5-point grading scheme. Differences between strains were evaluated using either one way ANOVA or Kruskal-Wallis test.
Results:
The presence of the nee allele caused a marked elevation of IOP above that observed in control mice (+6.0 mmHg, p=0.0002), but no difference was observed with respect to the absence or presence of functional complement genes. The elevation in IOP caused a decline in RGC numbers and an increase in optic nerve damage scores. Among mice homozygous for the nee mutation, the observed damage was particularly marked in C1q-/- (-74.3%) mice and significantly higher than that observed in C3-/- mice or littermate controls (-33.6% and -32.3%, respectively, p<0.0001). Similarly, elevated IOP did increase optic nerve damage scores from an average of 1.2 in control mice to 1.9 in nee and 4.7 in C1q-/- mice.
Conclusions:
Our data demonstrate that absence of functional C1q, but not C3, worsens RGC and axonal damage in this glaucoma model. These results suggest that C1q activity is crucial in limiting glaucomatous damage. Furthermore, our findings indicate that absence of C3 has little effect on disease progression in this model.
Keywords: 531 ganglion cells •
568 intraocular pressure •
629 optic nerve