Regulation of Postsynaptic Retrograde Signaling by Presynaptic Exosome Release

Abstract

SUMMARY 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.

A Presynaptic Regulatory System Acts Transsynaptically via Mon1 to Regulate Glutamate Receptor Levels in Drosophila

“…The observation that presynaptically expressed DMon1 localizes to postsynaptic regions ( Figure 7) and our results from neuronal RNAi and rescue experiments support this possibility. The involvement of transsynaptic signaling in regulating synaptic growth and function has been demonstrated in the case of signaling molecules such as Ephrins, Wingless, and Syt4 (Contractor et al 2002;Korkut and Budnik 2009;Korkut et al 2013). In Drosophila, both Wingless and Syt4 are released by the presynaptic terminal via exosomes to mediate their effects in the postsynaptic compartment.…”

Extracellular vesicles and intercellular communication within the nervous system

“…EVs have also been implicated in controlling retrograde postsynaptic signaling that mediates activity-dependent presynaptic growth and quantal neurotransmitter release at the neuromuscular junction in Drosophila larvae (42). Synaptotagmin 4 (SYT4), which is critical for this retrograde postsynaptic signaling to the motor neuron, is delivered to the postsynaptic terminal in the muscle in EVs…”

Transmission, Development, and Plasticity of Synapses

“…Synaptotagmin 4 (Syt4) was identified as a postsynaptic Ca 2+ sensor required for several forms of plasticity at the NMJ, such as the synaptic overgrowth of hyperexcitability mutants, the induction of presynaptic miniature release following high-frequency stimulation, or the induction of ghost boutons (Yoshihara et al 2005;Barber et al 2009;Korkut et al 2013;Piccioli and Littleton 2014). The retrograde molecules released in a Syt4-dependent manner have yet to be identified.…”

“…The retrograde molecules released in a Syt4-dependent manner have yet to be identified. Interestingly, recent work established that Syt4 is transferred transsynaptically from the presynaptic terminal on exosomes (Korkut et al 2013). Exosomes are signaling vesicles released from cells and are increasingly recognized to have important functions in cell-cell communication events (Cocucci and Meldolesi 2015).…”