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Genetic basis of age-dependent synaptic abnormalities in the retina

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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.

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Acknowledgments

The authors thank Satoshi Kinoshita for generation of frozen sections, Sharolyn Kawakami-Schulz for assistance with R/qtl, Joel Wipperfurth for assistance in genetic mapping, and the University of Wisconsin-Madison Genetics Confocal Facility for use of the confocal microscope. This work was supported by Grants from the National Institutes of Health (NIH R21 EY023061 and R01 EY022086), a professorship from the Retina Research Foundation (Walter H. Helmerich Research Chair), Core Grant for Vision Research (P30 EY016665) and a core Grant to Waisman Center (NIH P30 HD003352). Support for E.L.M. was partially provided by the NIH predoctoral training program in Genetics (NIH T32 GM007133).

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Authors and Affiliations

  1. Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI, 53706, USA

    Hitoshi Higuchi, Erica L. Macke, Wei-Hua Lee, Sam A. Miller, James C. Xu, Sakae Ikeda & Akihiro Ikeda

  2. McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI, 53706, USA

    Sakae Ikeda & Akihiro Ikeda

Authors
  1. Hitoshi Higuchi
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  2. Erica L. Macke
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  3. Wei-Hua Lee
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  4. Sam A. Miller
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  5. James C. Xu
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  6. Sakae Ikeda
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  7. Akihiro Ikeda
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Correspondence to Akihiro Ikeda.

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Hitoshi Higuchi, Erica L. Macke have contributed equally to this work.

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Higuchi, H., Macke, E.L., Lee, WH. et al. Genetic basis of age-dependent synaptic abnormalities in the retina. Mamm Genome 26, 21–32 (2015). https://doi.org/10.1007/s00335-014-9546-7

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  • DOI: https://doi.org/10.1007/s00335-014-9546-7

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