Amphisome biogenesis couples synaptic autophagy to local protein synthesis

Synaptic neurotransmission imposes high demands on membrane turnover, metabolism, and the remodeling of presynaptic molecular composition. While the impact of autophagy on neurotransmission has been firmly established, evidence for activity-dependent synaptic induction of autophagy remains surprisingly limited. Here, we demonstrate that amphisomes containing BDNF/TrkB are formed at presynaptic boutons following sustained synaptic activation. Activity-dependent bulk endocytosis serves as a membrane source for amphisome biogenesis, while key autophagy proteins are recruited to the active zone, and autophagy initiation is triggered locally by the energy-sensing kinase AMPK. BDNF/TrkB-containing amphisomes contribute to the turnover of key presynaptic cytoskeletal proteins involved in synaptic vesicle clustering. The formation of amphisomes following sustained synaptic activity facilitates both the degradation of these proteins and their replenishment through local translation of their mRNAs at presynaptic boutons. We propose that activity-induced synaptic autophagy largely reflects amphisome formation, which in turn is required for the replacement of proteins within the local presynaptic cytomatrix.