Cellular and Molecular Life Sciences

, Volume 70, Issue 10, pp 1831–1847 | Cite as

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

  • Stylianos MichalakisEmail author
  • Karin Schäferhoff
  • Isabella Spiwoks-Becker
  • Nawal Zabouri
  • Susanne Koch
  • Fred Koch
  • Michael Bonin
  • Martin Biel
  • Silke HaverkampEmail author
Research Article


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.


Cyclic nucleotide-gated channel Retinitis pigmentosa Horizontal cell Bipolar cell Synaptic plasticity Ectopic synapse 



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).

Supplementary material

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Copyright information

© Springer Basel 2012

Authors and Affiliations

  • Stylianos Michalakis
    • 1
    Email author
  • Karin Schäferhoff
    • 2
  • Isabella Spiwoks-Becker
    • 3
  • Nawal Zabouri
    • 4
  • Susanne Koch
    • 1
  • Fred Koch
    • 1
  • Michael Bonin
    • 2
  • Martin Biel
    • 1
  • Silke Haverkamp
    • 4
    Email author
  1. 1.Center for Integrated Protein Science Munich CiPSM and Department of Pharmacy – Center for Drug ResearchLudwig-Maximilians-Universität MünchenMunichGermany
  2. 2.Institute of Medical Genetics and Applied GenomicsUniversity Hospital TübingenTuebingenGermany
  3. 3.Institute for Microscopic Anatomy and NeurobiologyUniversity Medicine MainzMainzGermany
  4. 4.NeuroanatomyMax-Planck-Institute for Brain ResearchFrankfurtGermany

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