Regulation of Postsynaptic Retrograde Signaling by Presynaptic Exosome Release

Retrograde signals from postsynaptic targets are critical during development and plasticity of synaptic connections. These signals serve to adjust the activity of presynaptic cells according to postsynaptic cell outputs and to maintain synaptic function within a dynamic range. Despite their importance, the mechanisms that trigger the release of retrograde signals and the role of presynaptic cells in this signaling event are unknown. Here we show that a retrograde signal mediated by Synaptotagmin 4 (Syt4) is transmitted to the postsynaptic cell through anterograde delivery of Syt4 via exosomes. Thus, by transferring an essential component of retrograde signaling through exosomes, presynaptic cells enable retrograde signaling. ► Synaptotagmin 4 functions as a retrograde signal for presynaptic growth and function ► Syt4 is probably produced by pre- but not by postsynaptic cells ► Syt4 is transferred from pre- to postsynaptic compartments via exosomes ► This mechanism implies a presynaptic control of postsynaptic retrograde signaling Postsynaptic cells regulate presynaptic cells by releasing retrograde signals, one of which requires Synaptotagmin 4. Korkut et al. show that Synaptotagmin 4 is produced in presynaptic neurons and transferred to postsynaptic cells via exosomes, thus controlling retrograde signaling by postsynaptic cells.