“Exosome release facilitates rapid synaptic strengthening in LTP”
Exosomes are newly identified extracellular vesicles derived from endosomes. Until now, our understanding of the importance of exosomes has been limited to pathological contexts such as cancer or neurodegeneration. Although neuronal exosomes (NEs) were identified nearly a decade ago, their physiological significance remain largely unknown. Here we report that, NEs are released shortly after the induction of long-term potentiation (LTP) and are required for early phase LTP formation. We found a panel of exosome proteins that exhibited a significant regression-recovery pattern shortly after chemical LTP (cLTP) induction. This process reflected rapid NE dynamics, which was confirmed by real-time monitoring exosome release. We identified many postsynaptic proteins, including GluA2 in purified NEs by mass spectrometry. Interestingly, blocking NE synthesis or trafficking greatly impaired dynamic AMPAR insertion in postsynaptic membranes. Furthermore, potentiation of miniature excitatory postsynaptic current (mEPSC) amplitudes was largely abolished by pre-incubation of neurons with an exosome synthesis inhibitor. The mechanisms that regulate the post-synaptic proteome to cause plasticity of synapses are not well defined. Therefore, rapid NE release potentially provides one such mechanism to unlock synapses and facilitate rearrangement of discrete synaptic proteins, which is a necessary step for synaptic strengthening during LTP formation. Overall, we reveal a critical physiological role of NEs, and discover a key cellular process underlying synaptic potentiation that may be fundamental to regulating synaptic efficacy.