Abstract
Activity is thought to guide the patterning of synaptic connections in the developing nervous system. Specifically, differences in the activity of converging inputs are thought to cause the elimination of synapses from less active inputs and increase connectivity with more active inputs1,2. Here we present findings that challenge the generality of this notion and offer a new view of the role of activity in synapse development. To imbalance neurotransmission from different sets of inputs in vivo, we generated transgenic mice in which ON but not OFF types of bipolar cells in the retina express tetanus toxin (TeNT). During development, retinal ganglion cells (RGCs) select between ON and OFF bipolar cell inputs (ON or OFF RGCs) or establish a similar number of synapses with both on separate dendritic arborizations (ON-OFF RGCs). In TeNT retinas, ON RGCs correctly selected the silenced ON bipolar cell inputs over the transmitting OFF bipolar cells, but were connected with them through fewer synapses at maturity. Time-lapse imaging revealed that this was caused by a reduced rate of synapse formation rather than an increase in synapse elimination. Similarly, TeNT-expressing ON bipolar cell axons generated fewer presynaptic active zones. The remaining active zones often recruited multiple, instead of single, synaptic ribbons. ON-OFF RGCs in TeNT mice maintained convergence of ON and OFF bipolar cells inputs and had fewer synapses on their ON arbor without changes to OFF arbor synapses. Our results reveal an unexpected and remarkably selective role for activity in circuit development in vivo, regulating synapse formation but not elimination, affecting synapse number but not dendritic or axonal patterning, and mediating independently the refinement of connections from parallel (ON and OFF) processing streams even where they converge onto the same postsynaptic cell.
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Acknowledgements
We are grateful to J. Sanes and R. W. Burgess for TeNT–CFP, S. Naganishi for the mGluR6 promoter fragment, A. M. Craig for PSD95–CFP and R. Y. Tsien for tdTomato. We thank F. Soto, L. Godinho, A. Lewis, F. Dunn and T. Misgeld for comments on the manuscript. This work was supported by the National Institutes of Health (R.O.L.W., EY10699, J.L.M. T32 EY07031), the McDonnell Foundation at Washington University (R.O.L.W.), National Eye Institute core grant (E.D.P., EY01730) and the Deutsche Forschungsgemeinschaft (D.K., KE 1466/1-1).
Author Contributions D.K. and R.O.L.W. conceived the experiments. D.K. and R.M.L. generated transgenic constructs. D.K. performed and analysed patch-clamp and multi-electrode array recordings, and imaging experiments on fixed tissue. D.K. and J.L.M. performed and analysed live imaging experiments. D.K., E.D.P. and R.O.L.W. carried out the ultrastructural analysis. D.K. and R.O.L.W. wrote the paper.
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This file contains a Supplementary Discussion, Supplementary Figures S1-S9 with Legends and Supplementary References. (PDF 1374 kb)
Supplementary Movie 1
This movie focuses through the representative RGC dendrite shown in Figure 2c expressing tdTomato (blue) and PSD95-CFP (red) in a P21 mGluR6-YFP/TeNT mouse (bipolar cell terminals in green). (MOV 2565 kb)
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Kerschensteiner, D., Morgan, J., Parker, E. et al. Neurotransmission selectively regulates synapse formation in parallel circuits in vivo. Nature 460, 1016–1020 (2009). https://doi.org/10.1038/nature08236
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DOI: https://doi.org/10.1038/nature08236
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