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Synapse maturation by activity-dependent ectodomain shedding of SIRPα.

Nature neuroscience | Oct 26, 2013

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.

Pubmed ID: 24036914 RIS Download

Mesh terms: Animals | Cells, Cultured | Excitatory Postsynaptic Potentials | Female | HEK293 Cells | Hippocampus | Humans | Male | Mice | Mice, Inbred C57BL | Mice, Knockout | Organ Culture Techniques | Protein Structure, Tertiary | Receptors, Immunologic | Synapses

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Associated grants

  • Agency: NIMH NIH HHS, Id: R01 MH091429
  • Agency: NICHD NIH HHS, Id: P30 HD018655
  • Agency: NIMH NIH HHS, Id: MH091429
  • Agency: NINDS NIH HHS, Id: NS070005
  • Agency: NIMH NIH HHS, Id: R21 MH092614
  • Agency: NINDS NIH HHS, Id: R01 NS070005
  • Agency: NIMH NIH HHS, Id: MH092614

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