Synapse maturation by activity-dependent ectodomain shedding of SIRP?.

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-? (SIRP?) mediates presynaptic maturation. Two target-derived molecules, fibroblast growth factor 22 and SIRP?, sequentially organize the glutamatergic presynaptic terminals during the initial synaptic differentiation and synapse maturation stages, respectively, in the mouse hippocampus. SIRP? drives presynaptic maturation in an activity-dependent fashion. Remarkably, neural activity cleaves the extracellular domain of SIRP?, 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, SIRP?-dependent synapse maturation has an impact on synaptic function and plasticity. Thus, ectodomain shedding of SIRP? is an activity-dependent trans-synaptic mechanism for the maturation of functional synapses.

SUBMITTER: Toth AB 

PROVIDER: S-EPMC3820962 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature