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Characterization of neurite outgrowth and ectopic synaptogenesis in response to photoreceptor dysfunction

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Abstract

In the mammalian retina, light signals generated in photoreceptors are passed to bipolar and horizontal cells via synaptic contacts. In various pathological conditions, these second-order neurons extend neurites into the outer nuclear layer (ONL). However, the molecular events associated with this neurite outgrowth are not known. Here, we characterized the morphological synaptic changes in the CNGA3/CNGB1 double-knockout (A3B1) mouse, a model of retinitis pigmentosa. In these mice, horizontal cells looked normal until postnatal day (p) 11, but started growing neurites into the ONL 1 day later. At p28, the number of sprouting processes decreased, but the remaining sprouts developed synapse-like contacts at rod cell bodies, with an ultrastructural appearance reminiscent of ribbon synapses. Hence, neurite outgrowth and ectopic synaptogenesis in the A3B1 retina were precisely timed events starting at p12 and p28, respectively. We therefore performed microarray analysis of retinal gene expression in A3B1 and wild-type mice at those ages to evaluate the genomic response underlying these two events. This analysis identified 163 differentially regulated genes in the A3B1 retina related to neurite outgrowth or plasticity of synapses. The global changes in gene expression in the A3B1 retina were consistent with activation of signaling pathways related to Tp53, Smad, and Stat3. Moreover, key molecules of these signaling pathways could be localized at or in close proximity to outgrowing neurites. We therefore propose that Tp53, Smad, and Stat3 signaling pathways contribute to the synaptic plasticity in the A3B1 retina.

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Acknowledgments

We thank G.-S. Nam, Ilse von Graevenitz and Jennifer Schmidt for technical assistance, Jeroen Pasterkamp (University Medical Center Utrecht) for helpful discussion on PlexinC1, and Heinz Wässle for financial support. Grant sponsor: Deutsche Forschungsgemeinschaft (DFG).

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Authors and Affiliations

  1. Center for Integrated Protein Science Munich CiPSM and Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr 7, 81377, Munich, Germany

    Stylianos Michalakis, Susanne Koch, Fred Koch & Martin Biel

  2. Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Calwerstr. 7, 72076, Tuebingen, Germany

    Karin Schäferhoff & Michael Bonin

  3. Institute for Microscopic Anatomy and Neurobiology, University Medicine Mainz, Mainz, Germany

    Isabella Spiwoks-Becker

  4. Neuroanatomy, Max-Planck-Institute for Brain Research, Deutschordenstrasse 46, 60528, Frankfurt, Germany

    Nawal Zabouri & Silke Haverkamp

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  1. Stylianos Michalakis
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  2. Karin Schäferhoff
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  3. Isabella Spiwoks-Becker
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  4. Nawal Zabouri
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  5. Susanne Koch
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  6. Fred Koch
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  7. Michael Bonin
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  8. Martin Biel
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  9. Silke Haverkamp
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Correspondence to Stylianos Michalakis or Silke Haverkamp.

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Michalakis, S., Schäferhoff, K., Spiwoks-Becker, I. et al. Characterization of neurite outgrowth and ectopic synaptogenesis in response to photoreceptor dysfunction. Cell. Mol. Life Sci. 70, 1831–1847 (2013). https://doi.org/10.1007/s00018-012-1230-z

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  • DOI: https://doi.org/10.1007/s00018-012-1230-z

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