Secreted Wnts play crucial roles in synaptogenesis and synapse maintenance, but endogenous factors promoting synapse elimination in central neurons remain unknown. Here we show that proline-rich 7 (PRR7) induces specific removal of excitatory synapses and acts as a Wnt inhibitor. Remarkably, transmembrane protein PRR7 is activity-dependently released by neurons via exosomes. Exosomal PRR7 is uptaken by neurons through membrane fusion and eliminates excitatory synapses in neighboring neurons. Conversely, PRR7 knockdown in sparse neurons greatly increases excitatory synapse numbers in all surrounding neurons. These non-cell autonomous effects of PRR7 are effectively negated by augmentation or blockade of Wnt signaling. PRR7 exerts its effect by blocking the exosomal secretion of Wnts, activation of GSK3β, and promoting proteasomal degradation of PSD proteins. These data uncover a proximity-dependent, reciprocal mechanism for the regulation of excitatory synapse numbers in local neurons and demonstrate the significance of exosomes in inter-neuronal signaling in the vertebrate brain.
Bibliographical noteFunding Information:
We thank Clive Wells at the MCW Electron Microscopy Core Facility for EM image acquisition and Dr. Wei Hsu (University of Rochester Medical Center) for providing myc-GPR177 construct. We also appreciate Casey Vickstrom and Christopher Olsen for reading the manuscript. This research was supported by Charles Jacobus Family Foundation, funding provided through the Research and Education Program, a component of the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin (S.H.L.), and NIH/DA035217 and MH101146 (Q.-s.L.).
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)