Early degeneration of photoreceptor synapse in Ccl2/Cx3cr1-deficient mice on Crb1rd8 background


  • J.Z. designed the experiments and conducted histology, electron microscopy, immunofluorescence, data analysis, and wrote the article. J.T. reviewed the article. X.C. and D.S. took care of the mice. W.L. and C.-C.C. participated in the design of the experiments, data analyses, and critical review of the manuscript. All authors approved the final article.

  • Published 2013. This article is a US Government work and, as such, is in the public domain of the United States of America.

Correspondence to: Chi-Chao Chan, 10 Center Dr., Bldg. 10, Rm. 10N103, NIH/NEI, Bethesda, MD 20892-1857, USA. E-mail: chanc@nei.nih.gov or Jun Zhang, 35 Convent Dr., Bldg. 35, Rm. 3C1004, NINDS/NIH, Bethesda, MD 20892 USA. E-mail: junzhang@ninds.nih.gov


Photoreceptor ribbon synapse releases glutamate to postsynaptic targets. The synaptic ribbon may play multiple roles in ribbon synapse development, synaptic vesicle recycling, and synaptic transmission. Age-related macular degeneration (AMD) patients appear to have fewer or no detectable synaptic ribbons as well as abnormal swelling in the photoreceptor terminals in the macula. However, reports on changes of photoreceptor synapses in AMD are scarce and photoreceptor type and quantity affected in early AMD is still unclear. Here, we employed multiple anatomical techniques to investigate these questions in Ccl2−/−/Cx3cr1−/− mouse on Crb1rd8 background (DKO rd8) at one month of age. We found that approximately 17% of photoreceptors over the focal lesion were lost. Immunostaining for synapse-associated proteins (CtBP2, synaptophysin, and vesicular glutamate transporter 1) showed significantly reduced expression and ectopic localization. Cone opsins demonstrated dramatic reduction in expression (S-opsins) and extensive mislocalization (M-opsins). Quantitative ultrastructural analysis confirmed a significant decrease in the number of cone terminals and nuclei, numerous vacuoles in remaining cone terminals, reduction in the number of synaptic ribbons in photoreceptor terminals, and ectopic rod ribbon synapses. In addition, glutamate receptor immunoreactivity on aberrant sprouting of rod bipolar cells and horizontal cells were identified at the ectopic synapses. These results indicate that synaptic alterations occur at the early stages of disease and cones are likely more susceptible to damage caused by DKO rd8 mutation. They provide a new insight into potential mechanism of vision function lost due to synaptic degeneration before cell death in the early stages of AMD. Synapse 67:515–531, 2013. © 2013 Wiley Periodicals, Inc.