Ccl2/Cx3cr1 knockout mice have inner retinal dysfunction but are not an accelerated model of AMD.
OBJECTIVE
The chemokine, Ccl2, and the fractalkine receptor, Cx3cr1, have both been implicated in the pathogenesis of age related macular degeneration (AMD), with mice lacking both genes exhibiting features of AMD by 3 months of age. However, recent reports indicate that this ascribed phenotype is due to the presence of a retinal degeneration mutation (crb1(rd8/rd8), rd8) on the background strain. Our aim was to characterize the retinal effects of lack of Ccl2 and Cx3cr1 (Ccl2(-/-)/Cx3cr1(EGFP/EGFP), CDKO-mice), in mice without the rd8 mutation.


METHODS
Nine-month-old, CDKO and wildtype C57blk6J mice were investigated for retinal fundus appearance and histology. The function of the rod and cone pathways was assessed using the ERG.


RESULTS
The CDKO mice did not develop lesions in the retinal fundus, and the ultrastructure of Bruch's membrane and the RPE were similar to that of C57blk6J mice. From the ERG, there was no change in the amplitude of the rod photoreceptor response, or in the rod or cone post-photoreceptor b-wave. However, the rod and cone ERG oscillatory potentials were significantly reduced in the CDKO animals, a phenotype apparent in Cx3cr1(EGFP/EGFP)- but not Ccl2(-/-)-founder lines. This correlated with aberrant amacrine cell morphology in the CDKO mice. In addition, Müller cells were gliotic and microglial morphology subtly altered, indicative of retinal stress.


CONCLUSIONS
These results suggest that in the absence of the rd8 mutation, the CDKO-mouse has a mild inner retinal phenotype characterized by altered amacrine cell function, but that it is not an accelerated model of AMD.
Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, Australia.
Kirstan A
KA
Vessey
Ursula
U
Greferath
Andrew I
AI
Jobling
Joanna A
JA
Phipps
Tracy
T
Ho
Michelle
M
Waugh
Erica L
EL
Fletcher
D000818:Animals; D016570:Bruch Membrane / Q000378:metabolism / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004596:Electroretinography; D005838:Genotype; D007150:Immunohistochemistry; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism* / Q000648:ultrastructure; D008854:Microscopy, Electron; D009154:Mutation; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure
D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine