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.

EndophilinA-dependent coupling between activity-dependent calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation

“…EndoA is required for Ca 2+ -induced pre-synaptic autophagy It is not known how neuronal activity induces autophagy at synapses (Decet and Verstreken, 2021;Shehata et al, 2012;Soukup et al, 2016;Wang et al, 2015). We therefore tested if Ca 2+ influx induced by stimulation can trigger the process.…”

“…There are several synapse-specific proteins that are implicated in the creation of autophagosomes at nerve terminals and these same proteins are not involved in autophagy elsewhere in the cell (Azarnia Tehran et al, 2018; Decet and Verstreken, 2021; Montenegro-Venegas et al, 2020; Soukup et al, 2016; Vanhauwaert et al, 2017). This includes the active zone protein Bassoon that binds to and sequesters Atg5, thus limiting the ability to create new autophagosomes at synapses (Okerlund et al, 2017).…”

“…This also causes protein stress and damage. An interesting idea is that this stress and damage are coupled to protein- and organelle-turnover including that, across species, neuronal activity induces the formation of autophagosomes at synapses (Decet and Verstreken, 2021; Hill et al, 2019; Kroemer et al, 2010; Kulkarni et al, 2021; Nakatogawa, 2020; Nixon, 2013; Shehata et al, 2012; Soukup et al, 2016; Wang et al, 2015; Yang et al, 2022). However, how elements of neuronal activity such as calcium influx, neurotransmitter release or endocytosis, drive the formation of autophagosomes at synaptic terminals has not been investigated.…”

“…(Sudhof, 2004;Südhof, 2013;Südhof and Malenka, 2008). Yet synapses are often located far from neuronal cell bodies and thus, nerve terminals need to, at least in part, locally cope with turnover of bio-molecules (Azarnia Tehran et al, 2018;Decet and Verstreken, 2021;Soukup et al, 2018;Vijayan and Verstreken, 2017;Wang et al, 2017).…”

Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling

“…This role of autophagy in neuronal homeostasis is especially crucial at synapses, which possess high metabolic demands and are vulnerable to accumulated damage and stress (reviewed in ( 15 )). Autophagy has been described to regulate the degradation of several pre- and postsynaptic proteins ( 12 , 54 – 56 ), axonal ER ( 13 ), and synaptic mitochondria ( 14 , 57 ) and, is, thereby, crucial for the regulation of synaptic plasticity, including long-term depression (LTD) ( 11 , 25 , 58 , 59 ). Intriguingly, here we find that ATG5-mediated autophagy does not primarily contribute to the regulation of bulk levels of SV and/or mitochondrial proteins in excitatory or inhibitory neurons i n-vivo .…”