FIGURE 1.

Cross-regulation between autophagy and synaptic vesicle cycling at the pre-synaptic terminal. At synapses, synaptic vesicle (SV) cycling and autophagy are interconnected and reciprocally regulated. Black lines indicate the effect on autophagosome formation elicited by components of the SV machinery, while red lines highlight the influence on neurotransmission evoked by changes in autophagy levels. The endocytic proteins EndoA and Synj1 participate in autophagosome formation respectively by recruiting ATG3 and by allowing ATG18 to cycle off the autophagosomal membranes. Both actions result in the lipidation of ATG8/LC3. The scaffold protein Bassoon has the opposite effect. It sequesters ATG5 and prevents autophagosome formation. Pre-synaptic calcium waves are associated with autophagy induction, but a direct mechanistic link between the two is missing. Cycling of ATG9-positive vesicles facilitate autophagosome formation at pre-synaptic sites. The GTPase Rab26 clusters on SVs and by interacting with ATG16L it recruits the autophagy machinery that engulfs and degrades SVs. SV turnover modulates the strength of neurotransmission. Reduced numbers of SVs, due to autophagy-mediated clearance, results in decreased neurotransmitter release. An opposite effect is observed when autophagy is abolished and tubular ER accumulates at synapses. As a consequence, calcium buffering is altered and neurotransmission is enhanced. The crosstalk between synaptic autophagy and neurotransmission might represent a feedback mechanism that synapses employ to regulate both pathways in a flexible way.