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Synapse maturation by activity-dependent ectodomain shedding of SIRPα

Abstract

Formation of appropriate synaptic connections is critical for proper functioning of the brain. After initial synaptic differentiation, active synapses are stabilized by neural activity-dependent signals to establish functional synaptic connections. However, the molecular mechanisms underlying activity-dependent synapse maturation remain to be elucidated. Here we show that activity-dependent ectodomain shedding of signal regulatory protein-α (SIRPα) mediates presynaptic maturation. Two target-derived molecules, fibroblast growth factor 22 and SIRPα, sequentially organize the glutamatergic presynaptic terminals during the initial synaptic differentiation and synapse maturation stages, respectively, in the mouse hippocampus. SIRPα drives presynaptic maturation in an activity-dependent fashion. Remarkably, neural activity cleaves the extracellular domain of SIRPα, and the shed ectodomain in turn promotes the maturation of the presynaptic terminal. This process involves calcium/calmodulin-dependent protein kinase, matrix metalloproteinases and the presynaptic receptor CD47. Finally, SIRPα-dependent synapse maturation has an impact on synaptic function and plasticity. Thus, ectodomain shedding of SIRPα is an activity-dependent trans-synaptic mechanism for the maturation of functional synapses.

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Figure 1: FGF22 and SIRPα promote the early or late stage of glutamatergic presynaptic differentiation, respectively.
Figure 2: SIRPα is required for the maturation, but not induction or maintenance, of excitatory presynaptic terminals in the hippocampus in vivo.
Figure 3: Cleavage of the extracellular domain of SIRPα is activity-dependent and is necessary for SIRPα-dependent presynaptic maturation.
Figure 4: SIRPα-dependent presynaptic maturation involves calcium channels, CaMK and MMP.
Figure 5: CD47 is the presynaptic receptor for SIRPα-mediated presynaptic maturation.
Figure 6: Impact of SIRPα-dependent presynaptic maturation on synaptic plasticity.

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Acknowledgements

We thank J. Sanes for critical comments on the manuscript; H. Enomoto for pSV loxP sv40 intron polyA EGFP FRTneo plasmid; A. Murayama and L. Kee for plasmid construction; E. Gibbs for help with in situ hybridization; D. Sorenson for help with electron microscopy; M. Zhang, R. Carson and A. Williams for technical assistance; and E. Hughes, Y. Qu, K. Childs, G. Gavrilina, D. Vanheyningen and the Transgenic Animal Model Core of the University of Michigan for preparation of SIRPα knockout mice. Core support was provided by the University of Michigan Center for Organogenesis. This work was supported by the Ester A. & Joseph Klingenstein Fund, the Edward Mallinckrodt Jr. Foundation, the March of Dimes Foundation, the Whitehall Foundation and US National Institutes of Health grants MH091429, NS070005 and MH092614 (H.U.).

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H.U. designed experiments and prepared the manuscript. A.B.T., A.T., L.Y.Z., E.M.J.-V. and D.J.L. performed experiments. M.A.S. and H.U. supervised the project. All authors analyzed data and commented on the manuscript.

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Correspondence to Hisashi Umemori.

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Toth, A., Terauchi, A., Zhang, L. et al. Synapse maturation by activity-dependent ectodomain shedding of SIRPα. Nat Neurosci 16, 1417–1425 (2013). https://doi.org/10.1038/nn.3516

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