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Genetic basis of age-dependent synaptic abnormalities in the retina

Author:
Higuchi, Hitoshi, Macke, Erica L., Lee, Wei-Hua, Miller, Sam A., Xu, James C., Ikeda, Sakae, Ikeda, Akihiro
Source:
Mammalian genome 2015 v.26 no.1-2 pp. 21-32
ISSN:
0938-8990
Subject:
chromosome mapping, chromosome substitution, chromosomes, gene expression regulation, genome, humans, inflammation, macular degeneration, mice, phenotype, photoreceptors, quantitative trait loci, retina, substitution lines, synapse
Abstract:
Understanding the normal aging process will help us determine the mechanisms of how age-related diseases are caused and progress. A/J inbred mice have been shown to exhibit accelerated aging phenotypes in the retina including increased inflammation and photoreceptor cell degeneration, which resemble human aging symptoms. C57BL/6J (B6) inbred mice are less susceptible for these abnormalities, indicating the existence of genetic factor(s) that affect their severity. In this study, we determined that another age-dependent phenotype, ectopic synapse formation, is also accelerated in the A/J retina compared to the B6 retina. Through genetic mapping utilizing recombinant inbred strains, we identified quantitative trait loci (QTLs) on chromosome 7 and 19, which contribute to abnormal retinal synapses as well as other age-dependent phenotypes. Using consomic single chromosome substitution lines where a single chromosome is from A/J and the rest of the genome is B6, we investigated the individual effect of each QTL on retinal aging phenotypes. We observed that both QTLs independently contribute to abnormal retinal synapses, reduction in the number of cone cells, and an up-regulation of retinal stress marker, glial fibrillary acidic protein (GFAP). Mice with a single chromosome substitution on chromosome 19 also exhibited an increase in inflammatory cells, which is characteristic of aging and age-related macular degeneration. Thus, we identified QTLs that are independently capable of affecting the severity and progression of age-dependent retinal abnormalities in mice.
Agid:
1201871