title: Differential Effects of C1qa Ablation on Glaucomatous Damage in Two Sexes in DBA/2NNia Mice.
abstract: OBJECTIVE
  To determine the sex and age-related effects of C1qa ablation on retinal ganglion cell (RGC) and optic nerve (ON) axonal loss in a mouse model of glaucomatous neurodegeneration.
  
  
  METHODS
  Congenic C1qa mice were generated in the DBA/2NNia background. Female and male knockout (-/-), heterozygous (+/-), and wild type (+/+) mice were aged up to 14 months and IOPs were recorded in a subset of animals. Retinas of mice from all three groups at 5-6, 9-10 and 11-13 months of age were flat-mounted after retrograde labeling with Fluorogold. Imaged retinas were scored (RGC score) semi-quantitatively on a 10 point scale by two independent observers. A subset of retinas and optic nerves were also used for measurement of total number of RGCs. Semi-thin sections of ON were imaged and graded (ON score) for the amount of axonal damage semi-quantitatively, by two masked observers. Analysis of covariance (ANCOVA) was used for statistical comparisons. Microglial cells in flat-mounted retinas of 5-6 month old C1qa -/- and C1qa +/+ mice were used for assessment of microglial activation utilizing morphological criteria.
  
  
  RESULTS
  Female C1qa -/- mice had significantly higher IOP (p<0.000001, ANOVA) between 8 and 13 months of age compared to C1qa +/+ animals. No differences in IOPs between animals of the three genotypes were observed in males. At 5-6 months of age, there was no difference in RGC or ON scores between the three genotypes in animals of either sex. At 9-10 months of age, female mice didn't show significant differences in RGC or ON scores between the three genotypes. However, male C1qa -/- and C1qa +/- mice of the same age had better RGC and ON scores (p<0.003 and p<0.05, ANCOVA, for RGC and ON scores, respectively) compared with C1qa +/+ mice. At 11-13 months of age, female C1qa -/- mice had better RGC scores (p<0.006, ANCOVA) compared to C1qa +/+ and C1qa +/- animals. Accordingly, C1qa -/- mice had higher RGC counts (p<0.03, t-test) compared to C1qa +/+ animals. In male mice, there was a tendency for 12 month old C1qa -/- animals to have better RGC scores and higher RGC counts, but this didn't reach statistical significance. ON scores in 11-13 month old animals of either sex were not different between all three genotype. Microglial activation in male 5-6 month old C1qa -/- mice was decreased compared to C1qa +/+ animals; no such effect was seen in females.
  
  
  CONCLUSIONS
  Absence of C1qa ameliorates RGC and ON loss in the DBA/2NNia strain, but this effect differs between the two sexes. C1q-mediated RGC damage seems to be more potent than IOP-mediated RGC loss. In contrast, C1qa absence provides axonal protection early on, but this protection cannot overcome the effects of significant IOP elevation.
authors.affiliation: Department of Cell Biology, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, United States of America.|State University of New York (SUNY) Eye Institute, Brooklyn, New York, United States of America.
authors.forename: Ruma
authors.initials: R
authors.lastname: Kumari
authors.affiliation: Department of Cell Biology, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, United States of America.|State University of New York (SUNY) Eye Institute, Brooklyn, New York, United States of America.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Astafurov
authors.affiliation: Department of Ophthalmology, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, United States of America.|State University of New York (SUNY) Eye Institute, Brooklyn, New York, United States of America.
authors.forename: Alina
authors.initials: A
authors.lastname: Genis
authors.affiliation: Department of Cell Biology, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, United States of America.|Department of Ophthalmology, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, United States of America.|State University of New York (SUNY) Eye Institute, Brooklyn, New York, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Danias
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D015922:Complement C1q / Q000235:genetics / Q000502:physiology*; D005260:Female; D055786:Gene Knockout Techniques; D008297:Male; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D012737:Sex Factors
chemical_list: D015922:Complement C1q