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    • In spite of decades of

    2022-01-26

    In spite of decades of research the mechanisms of SV endocytosis and recycling remain controversial. Accumulating evidence suggests that SV endocytosis occurs by more than one mechanism (e.g. clathrin-independent endocytosis, clathrin-mediated endocytosis, bulk endocytosis; reviewed in (Dittman and Ryan, 2009, Kononenko and Haucke, 2015, Murthy and De Camilli, 2003, Soykan et al., 2016, Wu et al., 2014a)) and operates on various timescales that range from hundreds of milliseconds (e.g. ultrafast endocytosis) to tens of seconds (Delvendahl et al., 2016, Koenig and Ikeda, 1996, Smith et al., 2008, Soykan et al., 2017, Watanabe et al., 2013, Wu et al., 2014a), depending on the synapse and the stimulus. Recent data further show that endocytic SV membrane retrieval and the reformation of functional SVs by clathrin-mediated PF-5274857 are separable processes (Kononenko et al., 2014, Soykan et al., 2017, Watanabe et al., 2014), which likely is of importance for understanding the mechanisms of exo-endocytic coupling as discussed below. At synapses of mature neurons SV exocytosis is tightly controlled in space and time and occurs preferentially, if not exclusively, at the AZ, a platform linking Ca2+ influx to rapid soluble NSF-attachment protein receptor (SNARE)-driven SV fusion. The AZ membrane is decorated by conserved large multi-domain proteins that include for example ELKS/CAST (the vertebrate homologs of Bruchpilot/BRP in Drosophila), the piccolo-bassoon family, RIM and RIM-binding proteins (RBPs), Munc13, and liprins (Gundelfinger and Fejtova, 2012, Petzoldt et al., 2016, Sudhof, 2012). These proteins form a three-dimensional electron-dense matrix sometimes referred to as presynaptic AZ cytomatrix that is thought to mediate the temporal and spatial coupling between the influx of Ca2+ through voltage-gated Ca2+-channels and SV fusion. AZ scaffolds are also linked directly or indirectly to the machinery for SV endocytosis and turnover (Gundelfinger and Fejtova, 2012, Haucke et al., 2011). The giant AZ protein piccolo, for instance, associates with the actin- and dynamin-binding protein Abp1 (Fenster et al., 2003), with the peripheral AZ scaffold GIT (Podufall et al., 2014) that interacts with the endocytic SV sorting adaptor Stonin 2 (termed stoned B in Drosophila; Phillips et al., 2010), and with the E3 ubiquitin ligase Siah1 (Waites et al., 2013). The AZ, thus, may not only serve as a spatiotemporal regulator of exocytosis but also as a site to coordinate SV recycling and protein turnover (Okerlund et al., 2017). Consistent with such a hypothetical function endocytic intermediates have been observed at the periphery of the AZ membrane in synapses stimulated optogenetically with single or few action potentials (APs) (Watanabe et al., 2013), while strong repetitive stimulation causes endocytosis to mainly operate at a distance from the AZ, in the periactive zone area (Gad et al., 1998).
    Matching presynaptic exocytosis and endocytosis Electrophysiological capacitance measurements at large synapses such as the calyx of Held or cerebellar mossy fiber boutons and optical recordings based on styryl dyes or pHluorin-tagged SV protein chimeras indicate that Ca2+-triggered SV exocytosis is accompanied by compensatory endocytic membrane and SV protein retrieval (Balaji and Ryan, 2007, Delvendahl et al., 2016, Dittman and Ryan, 2009, Haucke et al., 2011, Smith et al., 2008, Wu et al., 2014a, Wu et al., 2007, Yamashita et al., 2005). Evidence for the formation of shallow endocytic pits after exocytic SV fusion has been gathered from electron microscopy (EM) imaging of chemically or electrically stimulated synapses (Dittman and Ryan, 2009, Kononenko and Haucke, 2015, Murthy and De Camilli, 2003) and, more recently, from high-pressure freeze EM analysis of optogenetically stimulated neurons expressing channelrhodopsin (Watanabe et al., 2013, Watanabe et al., 2014). For most stimulation paradigms compensatory SV membrane retrieval appears to match the amount of newly exocytosed SV membranes inserted into the plasma membrane, suggesting that endocytosis serves to maintain presynaptic membrane homeostasis thereby preventing boutons from swelling or shrinking. In some synapses endocytic overshoot, i.e. endocytosis that retrieves more membrane than the amount of exocytosed SVs, has been observed following prolonged high-frequency stimulation with AP-like trains (Wu et al., 2014a, Wu et al., 2007). The physiological relevance of this overshoot response is uncertain. How the synapse determines the exact number of exocytosed SVs or the amount of fused SV membranes remains a crucial unresolved question.