Abstract
Spontaneous activity generated in the retina is necessary to establish a precise retinotopic map, but the underlying mechanisms are poorly understood. We demonstrate here that neural activity controls ephrin-A–mediated responses. In the mouse retinotectal system, we show that spontaneous activity of the retinal ganglion cells (RGCs) is needed, independently of synaptic transmission, for the ordering of the retinotopic map and the elimination of exuberant retinal axons. Activity blockade suppressed the repellent action of ephrin-A on RGC growth cones by cyclic AMP (cAMP)-dependent pathways. Unexpectedly, the ephrin-A5–induced retraction required cAMP oscillations rather than sustained increases in intracellular cAMP concentrations. Periodic photo-induced release of caged cAMP in growth cones rescued the response to ephrin-A5 when activity was blocked. These results provide a direct molecular link between spontaneous neural activity and axon guidance mechanisms during the refinement of neural maps.
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Acknowledgements
We thank P. Vanderhaeghen for his help and advice concerning the ephrins, E. Welker for the gift of the brl mice and J.A. Girault, L. Maroteaux, C. Métin and V. Setola for discussions and suggestions. Part of this work was done at the Imaging core facility of Institut Fédératif de Recherche de Neurosciences de la Salpêtrière, with the expert help of C.M. Bachelet. This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale, Agence Nationale de la Recherche (APV05187DSA), and Retina France. X.N. was supported by a grant from the Délégation Générale pour l'Armement. N.N.-N. was supported by a grant from Ligue Française Contre l'Epilepsie.
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X.N. participated in the design of the project, the writing of the manuscript and conducted the experiments; S.V., A.M. and N.N.-N. conducted crucial experiments with the cocultures and the collapse assays; T.C.S. generated the munc18-1−/− mice and helped in the design of the project and the writing of the manuscript; R.M. contributed to the electrophysiological experiments and helped to write the manuscript; P.G. supervised the project and wrote the manuscript.
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Supplementary information
Supplementary Fig. 1
Calculation of a refinement index of the retinal projections. (PDF 273 kb)
Supplementary Fig. 2
TTX does not increase cell death in the SC and in the retina. (PDF 60 kb)
Supplementary Fig. 3
Summary of results and proposed mechanisms. (PDF 242 kb)
Supplementary Video 1
TTX blocks the rearward movement of growth cone in response to ephrin-A5. (AVI 5423 kb)
Supplementary Video 2
Ephrin-A5 induced axon retraction, blocked by TTX, is rescued by periodic cAMP uncaging. (AVI 8159 kb)
Supplementary Video 3
cAMP oscillations do not induce modifications in axon growth or retraction by themselves. (AVI 2953 kb)
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Nicol, X., Voyatzis, S., Muzerelle, A. et al. cAMP oscillations and retinal activity are permissive for ephrin signaling during the establishment of the retinotopic map. Nat Neurosci 10, 340–347 (2007). https://doi.org/10.1038/nn1842
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DOI: https://doi.org/10.1038/nn1842
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