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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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.).
The authors declare no competing financial interests.
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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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