Presynaptic Autophagy and the Connection With Neurotransmission

Abstract

Autophagy is an evolutionary conserved catabolic pathway essential for the maintenance of cellular homeostasis. Defective proteins and organelles are engulfed by autophagosomal membranes which fuse with lysosomes for cargo degradation. In neurons, the orchestrated progression of autophagosome formation and maturation occurs in distinct subcellular compartments. For synapses, the distance from the soma and the oxidative stress generated during intense neuronal activity pose a challenge to maintain protein homeostasis. Autophagy constitutes a crucial mechanism for proper functioning of this unique and vulnerable cellular compartment. We are now beginning to understand how autophagy is regulated at pre-synaptic terminals and how this pathway, when imbalanced, impacts on synaptic function and -ultimately- neuronal survival. We review here the current state of the art of "synaptic autophagy", with an emphasis on the biogenesis of autophagosomes at the pre-synaptic compartment. We provide an overview of the existing knowledge on the signals inducing autophagy at synapses, highlight the interplay between autophagy and neurotransmission, and provide perspectives for future research.

Keywords: macroautophagy; neurotransmission; synapse; synaptic autophagy; vesicle cycling.

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.