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Presynaptic Membrane Retrieval and Endosome Biology: Defining Molecularly Heterogeneous Synaptic Vesicles

Jennifer R. Morgan1, Heather Skye Comstra2,3, Max Cohen3, and Victor Faundez2,3

1Eugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods Hole, Massachusetts 02543 2Department of Cell Biology, Emory University, Atlanta, Georgia 30322 3School of Medicine, Emory University, Atlanta, Georgia 30322 Correspondence: [email protected]; [email protected]

The release and uptake of neurotransmitters by synaptic vesicles is a tightly controlled process that occurs in response to diverse stimuli at morphologically disparate synapses. To meet these architectural and functional synaptic demands, it follows that there should be diversity in the mechanisms that control their secretion and retrieval and possibly in the composition of synaptic vesicles within the same terminal. Here we pay particular attention to areas where such diversity is generated, such as the variance in exocytosis/endocytosis coupling, SNAREs defining functionally diverse populations and the adaptor-dependent sorting machineries capable of generating vesicle diversity. We argue that there are various synaptic vesicle recycling pathways at any given synapse and discuss several lines of evidence that support the role of the endosome in synaptic vesicle recycling.

hemical synapses contain discrete numbers “whisper,” whereas others “shout.” The “loud- Cof synaptic vesicles, which are capable of er” the synapse, the more synaptic vesicles are sustaining neurotransmitter release. Sustained required, extending from a few hundred vesicles neurotransmission occurs despite the secretory (whisperers) to nearly thousands (shouters). demands imposed by persistent and diverse pat- This beautiful analogy implies that every syn- terns of neuronal electrical activity. Maintaining apse has just one “voice” or species of vesicle. synaptic vesicle numbers requires local mecha- Here we will present the case that synapses are nisms to regenerate these vesicles to prevent more like choirs in which multiple vesicle spe- their exhaustion, preserve plasma membrane cies or “voices” contribute to the “pianissimo” surface area, and to maintain the molecularly or “fortissimo” parts of chemical neurotrans- distinct identity of a vesicle versus plasma mem- mission. brane. Rizzoli and Betz (2005) eloquently draw a Synaptic terminals show a range of struc- parallel between chemical neurotransmission tural and functional differences in distinct re- with synapse chatter saying that some synapses gions of the brain, suggesting that the mecha-

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nisms for exocytosis/endocytosis coupling, as mogenously distributed in vesicles except for well as local vesicle recycling, may also be di- limited differences in neurotransmitter trans- verse. On one side, the Calyx of Held nerve ter- porters (Gronborg et al. 2010). Morgenthaler minal participates in fast and sustained synaptic et al. (2003) pioneered the notion that there transmission at high frequency (800 Hz), which is heterogeneity in the molecular composition is crucial for sound localization in the auditory of synaptic vesicles in the same neuron. These brainstem (Taschenberger and von Gersdorff authors observed that synapses from the same 2000; Borst and Soria van Hoeve 2012). The Ca- neuron contain different amounts of synaptic lyx of Held houses 70,000 synaptic vesicles vesicle markers (Morgenthaler et al. 2003). The with nearly 3000 vesicles docked per Calyx ter- vesicle heterogeneity concept has received fur- minal. These docked vesicles are distributed ther support from biochemical, electrophysio- across the 500 active zones that exist per Calyx logical, and electron microscopy studies, all of where vesicle fusion occurs (Satzler et al. 2002). which suggest molecular heterogeneity among On the other hand, hippocampal synapses fire synaptic vesicles that carry the zinc transporter action potentials at 0.5 Hz in bursts (Dobrunz 3 (ZnT3) within the same terminal (Salazar et and Stevens 1999). This synapse contains 200 al. 2004; Lavoie et al. 2011). Similarly, im- synaptic vesicles and one with 10 munoelectron microscopy of the vesicular glu- vesicles docked (Schikorski and Stevens 1997). tamate transporter 2 (VGLUT2) and the vesicu- With such awide functional and structural gam- lar GABAtransporter (VGAT) showsthat within ut of synapses, it is reasonable to hypothesize the same terminals, both transporters localize to that synaptic vesicles may differ in their retrieval distinct populations of synaptic vesicles (Boul- mechanisms, not just at the rate at which the land et al. 2009). process occurs but also in the molecular path- The study of vesicular SNAREs (v-SNAREs) ways used. VAMP2, VAMP4, VAMP7, and Vti1a provides Two synaptic vesicle retrieval mechanisms, new ways to examine molecularly and function- namely /AP-2/-dependent bio- ally distinct synaptic vesicle pools in the same genesis and kiss-and-run, have been summa- nerve terminals. In studying VAMP7’s role in rized in outstanding recent reviews (see, for ex- spontaneous vesicle release, Scheuber et al. ample, Augustine et al. 2006; Rizzoli and Jahn brought these “noncanonical” synaptic vesicle 2007; Smith et al. 2008; Royle and Lagnado v-SNAREs to the spotlight (Scheuber et al. 2010; Ferguson and De Camilli 2012; Saheki 2006). The participation of these “noncanoni- and De Camilli 2012). Therefore, here we focus cal” synaptic vesicle v-SNAREs is also founded on the coupling of secretion and membrane re- on synaptic phenotypes of mouse and flies lack- trieval, as well as endosome sorting. We will ing the “canonical” synaptic vesicle v-SNARE, discuss new developments supporting the exis- VAMP2. VAMP2-null synapses possess severely tence of diverse functional and molecular pools impaired stimulus-evoked neurotransmitter se- of synaptic vesicles and how endocytosis and cretion, yet other forms of neurotransmission endosome retrieval mechanisms may generate such as spontaneous neurotransmitter release these vesicle pools. and hypertonic sucrose-evoked responses re- main mostly unaffected (Broadie et al. 1995; Schoch et al. 2001). The concept emerging now NOT ALL VOICES ARE CREATED EQUAL: from “noncanonical” SNARE studies is that dif- MOLECULAR DIVERSITY OF SYNAPTIC ferent SNAREs define functionally distinct syn- VESICLES aptic vesicle populations: VAMP2 marks vesi- Functionally defined pools of synaptic vesicles cles destined for stimulus-evoked synchronous presume molecular differences in vesicle com- neurotransmitter secretion (Broadie et al. 1995; position(Rizzoli andBetz 2005;DenkerandRiz- Schoch et al. 2001). VAMP4defines vesicles that zoli 2010). However, until recently the model has undergo stimulus evoked asynchronous neu- been that synaptic vesicle components are ho- rotransmitter release (Raingo et al. 2012), and

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Heterogeneous Synaptic Vesicles

vesicles undergoing spontaneous release are 2009), whereas in other cases the existence of a marked by the presence of Vti1a and/or VAMP7 separate, fast endocytosis is disputed (Granseth (Scheuber et al. 2006; Hua et al. 2011; Raingo et al. 2006; Balaji and Ryan 2007). One recent etal.2012).Whether“noncanonical”v-SNAREs study using an improved, brighter pHlorin re- coexist with VAMP2needsthorough experimen- ported the surprising finding that two vesicles tal analysis. However, VAMP2 and VAMP7 are are recaptured after exocytosis of a single vesicle present in acommon population of synaptic ves- when cells are stimulated at low frequency (Zhu icles, suggesting that vesicles may differ in the et al. 2009). However, as stimulation frequency relative v-SNARE concentration per vesicle rath- increases, the number of endocytosed vesicles er than by absolute segregation of v-SNAREs precisely matches the number of vesicles pre- among vesicles (Newell-Litwa et al. 2009). This viously exocytosed (Zhu et al. 2009). Thus, dur- idea predicts that VAMP2may be present at dif- ing stimulated release there is tight coupling ferent ratios with other v-SNAREs in individual between exocytosis and endocytosis, although vesicles, as suggested bysingle vesicle quantifica- this can break down under low frequency stim- tion of VAMP2 content (Mutch et al. 2011). ulation in which single vesicle fusion events can The hypothesis of functional and molecular be resolved. The question arises, then, what are heterogeneity of synaptic vesicles within the the molecular mechanisms that ensure such same nerve terminal makes at least two predic- tight coupling between exocytosis and endocy- tions. First, it predicts diverse molecular mech- tosis? And, how is this tight coupling achieved, anisms controlling the coupling between exo- given that synapses express different modes of cytosis and vesicle retrieval and, second, it exocytosis(e.g.,evoked,spontaneous,asynchro- envisions sorting mechanisms and organelles nous) and endocytosis (e.g., fast, slow)? capable of assembling vesicles of different com- A growing body of evidence indicates that position, such as endosomes. Wediscuss the ev- calcium influx provides one of the critical mo- idence supporting these predictions in the fol- lecular links between exocytosis and endocyto- lowing sections. sis. It is well established that calcium influx through voltage-dependent calcium channels (VDCCs) serves as the trigger for evoked synap- COUPLING BETWEEN EXOCYTOSIS tic vesicle exocytosis and neurotransmitter re- AND ENDOCYTOSIS lease (Katz and Miledi 1967; Augustine 2001; Endocytic membrane retrieval at synapses is Jahn and Fasshauer 2012; Sudhof 2012). In ge- tightly coupled to exocytosis to maintain proper neral, calcium positively regulates the initiation, vesicle pools, and also to retain plasma mem- speed, and amount of vesicle endocytosis in a brane integrity (Heuser and Reese 1973; Ryan range of central and peripheral synapses in ver- 2006; Haucke et al. 2011; Koch and Holt 2012). tebrates and invertebrates (von Gersdorff and This concept is nicely illustrated by membrane Matthews 1994; Gad et al. 1998; Ales et al. capacitance measurements, where after an exo- 1999; Neves et al. 2001; Sankaranarayanan and cytic-dependent increase in capacitance, the ca- Ryan2001;KuromiandKidokoro2005;Wuetal. pacitance trace reliably decays back to baseline, 2005, 2009; Balaji et al. 2008; Yamashita 2012; indicating that the amount of endocytosed Yaoet al. 2012b). For a long time, it was assumed membrane is equal to that previouslyexocytosed that the calcium influx needed for synaptic ves- (Wu et al. 2007; Smith et al. 2008). The develop- icle endocytosis is through VDCCs on the pre- ment of a pH-sensitive GFP,pHlorin, was a ma- synaptic plasma membrane. Indeed a recent jor breakthrough for the field, because it allows study at the Calyx of Held synapse provides for direct visualization of exocytosis and endo- strong evidence that this is the case (Xue et al. cytosis in living nerve terminals (Miesenbock 2012).However,anotherstudy reportedapoten- et al. 1998). In some cases, the pHlorins have tial role for Flower, a synaptic vesicle-associated revealed two modes of endocytosis, fast and calcium channel, in linking exocytosis and en- slow (Gandhi and Stevens 2003; Zhu et al. docytosis (Yao et al. 2009), a finding that has

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J.R. Morgan et al.

since been challenged (Xue et al. 2012). Regard- velopmental state, and anatomical location of a less of the source of calcium, its influx seems to synapse. For example, the role of calmodulin at be a requirement for vesicle recycling at most the Calyx of Held depends on the stimulation synapses, providing a strong link with exocytic paradigm: at high levels of activity, calmodulin mechanisms. is required for synaptic vesicle endocytosis, Downstream from calcium influx, several whereas at low levels of activity it is not (Yao endocytic calcium sensors and effectors have and Sakaba 2012). At hippocampal synapses, been identified (Yamashitaet al. 2010). Calmod- calcium and calcineurin paradoxically slow the ulin, a calcium-binding , has been de- retrieval of single synaptic vesicles (Leitz and scribed as the calcium sensor for synaptic vesicle Kavalali 2011). Calcineurin also inhibits vesicle endocytosis at several synapses, including the endocytosis at the Drosophila neuromuscular Calyx of Held and chromaffin cells (Artalejo junction (Kuromi et al. 1997). The developmen- et al. 1996; Wu et al. 2009; Yao and Sakaba tal stage of a synapse also influences calcium- 2012). Calcineurin, a Ca2þ/calmodulin-depen- calmodulin requirements for membrane retriev- dent protein phosphatase, has also been im- al. Synaptic vesicle recycling becomes inde- plicated. Upon synaptic activity, calcineurin pendent of the calcium-calmodulin-calcineurin dephosphorylates a suite of involved pathway upon maturation of the Calyx of Held, in clathrin-mediated synaptic vesicle recycling (Yamashita et al. 2010), whereas the opposite is (e.g., dynamin, amphiphysin, synaptojanin), true at cerebellar granule cells (Smillie et al. thus triggering protein–protein interactions 2005). Still other studies implicate the existence that drive endocytosis (Marks and McMahon of an extracellular sensor for calcium in synaptic 1998; Cousin and Robinson 2001; Sun et al. vesicle endocytosis (Gad et al. 1998; Teng and 2010). is another calcium-bind- Wilkinson 2003). Thus, the most likely scenario ing protein that serves as a dual calcium sensor is that synapses use multiple mechanisms for for both exocytosis and endocytosis (Jahn and coupling exocytosis to endocytosis, depending Fasshauer2012;Sudhof2012;Yaoetal.2012a,b). on the level of synaptic activity, mode of vesicle During endocytosis, synaptotagmin interacts retrieval, and age of the synapse. Indeed, the with another set of proteins involved in cla- newly discovered molecular diversity of synap- thrin-mediated synaptic vesicle recycling, in- tic vesicles, described in the previous section, cluding AP-2 and stonin 2 (Ullrich et al. 1994; almost necessitates that synapses use multiple Jarousse and Kelly 2001; Diril et al. 2006). Final- mechanisms for coupling exocytosis to endocy- ly, calcium regulates the phosphorylation and tosis. A recent review suggests that the calcium- activity of the major PI(4,5)P2-synthesizing dependent regulation of endocytosis, like exocy- enzyme in brain (PIP kinase type 1g), which tosis, is coordinated through synaptic activity, generates a pool of PI(4,5)P2 required for re- intracellular calcium levels, and the spatial dif- cruitment of clathrin adaptors and nuclea- fusion of calcium, providing a nice guideline for tion of actin (Wenk et al. 2001; Di Paolo et al. how the field might approach this problem in 2004; Morgan et al. 2004). These studies suggest future studies (Yamashita 2012). An interesting a model whereby calcium-calmodulin-calci- possibility is that the five synaptotagmin iso- neurin-dependent mechanisms trigger the con- forms present in the synaptic vesicle proteome certed assembly of the clathrin machinery nec- may define vesicle pools that respond to differ- essary for synaptic vesicle endocytosis. ent calcium thresholds (Takamori et al. 2006). This model presents a circumscribed set of molecular mechanisms coupling exocytosis to endocytosis. However, a careful examination of ENDOSOMES AND SYNAPTIC VESICLE RECYCLING: REVISION OF A the literature indicates that the story is much “CONTROVERSY” more complex. In fact, the requirements for cal- cium-calmodulin during membrane retrieval After vesicle internalization, a growing body of are modulated by the stimulation frequency, de- evidence suggests that cargo and vesicular con-

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Heterogeneous Synaptic Vesicles

tents are sorted through a local presynaptic en- Table 1. Endosome markers detected in purified syn- dosomal pathway. Endosomes support multiple aptic vesicles essential cell functions such as nutrient uptake, Category Protein intracellular signaling, morphogenesis during GTPases Rab4 development, defense against pathogens, and Rab5 membrane recycling at the nerve terminal. En- Rab7 dosomes are acidic membrane bound organelles Rab11 accessible from the extracellular milieu by inter- Rab23 nalized tracers, yet discontinuous with the cell Rab32 surface. This functional and elemental defini- SNAREs VAMP3 tion has been refined by the time an extracellular VAMP4 VAMP7 tracer takes to reach an endosome (early versus Syntaxin6 late endosomes), by the endosome localization Syntaxin7 within cells with respect to the nucleus, by ultra- Syntaxin13 structural morphological signatures, and by a Vti1a growing list of molecular markers which include SNAP29 membrane and lumenal protein markers, rab Sec1-Munc18 (SM) Vps33b GTPases, SNAREs, and proteins that regulate proteins Vps45 rabs and SNARE functional states (Table 1) Transmembrane LAMP1 (Mukherjee et al. 1997; Conner and Schmid Synaptogyrin 2003; Maxfield and McGraw 2004; van Meel SCAMP3-5 and Klumperman 2008; Huotari and Helenius Coats Adaptor complex 1 (AP-1) 2011). The centrality of endosomes is highlight- Adaptor complex 3 ed by the observation that nearly a quarter of a (AP-3) mammalian genome encodes proteins that phe- Coat binding BLOC-1 () notypically modify endosomes as determined BLOC-1 (pallidin) in genome wide siRNA screens (Collinet et al. BLOC-1 (SNAPIN) 2010). Whereas the role of endosomes in synap- Lipid raft Flotillin tic vesicle membrane retrieval is controversial, Thy1 we argue below that cumulated functional, ul- Lipid binding/modification PI4KIIa trastructural, and genetic evidence, as well as the Snx5 presence of diverse endosome molecular mark- The table lists molecules present in synaptic vesicles ers at the nerve terminal (Table 1), substantially that also have been documented in endosomes or shown favors endosome participation in synaptic vesi- to affect endosome-morphology function in non-neuronal cells. Molecules were collated from Takamori et al. (2006). cle biogenesis. Moreover, we offera reassessment of a cornerstone study challenging the role of endosomes in retrieval. (10 Hz for 1–15 min) synaptic vesicles ac- Forty years ago Heuser and Reese and Cec- quire an extracellular tracer, whereas vesicle con- carelli independently studied vesicle recycling at tent per terminal is reduced. These two events frog neuromuscular junctions using extracellu- happen concomitantly with the appearance of larly applied tracers. Their findings created two large membranous cisternae (Heuser and Reese nonexclusive models of membrane retrieval at 1973). Some of these cisternae are deep infolds the nerve terminal: one in which endosomes are of the cell surface (Fig. 1B, step 2), whereas oth- intermediaries in vesicle recycling (Fig. 1A,B), ers may be disconnected from the plasma mem- and a second model in which vesicles bypass brane, suggestive of endosomes (Fig. 1B, step 3). the need for an endosome intermediary (Cec- The formation of these cisternae under high- carelli et al. 1973; Heuser and Reese 1973; frequency electrical stimulation is known as Morgan et al. 2002). Heuser and Reese reported activity-dependent bulk endocytosis (Cousin that after high frequency electrical stimulation 2009). Importantly, synaptic vesicle depletion

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AB MVB 3 3 MVB

2 2

1 1 Active zone Active zone

Figure 1. Synaptic vesicle recycling mechanisms and the origins of synaptic vesicle species. (A,B) Mechanisms of vesicle recycling at the presynaptic terminal. Note that vesicles have different sizes only as a way to add depth to the diagram. Kiss-and-run retrieval of vesicle membrane has been omitted for simplicity. The insert in A denotes the region of the neuron magnified in both diagrams. A and B differ in the level of activity of the synapse. A represents a resting synapse in which spontaneous fusion of vesicles occurs at the active zone. Membrane is retrieved by clathrin-mediated endocytosis (steps 1–2) to an early endosome (step 3). This endosome is capable of sorting synaptic membrane proteins into different vesicles that repopulate the synaptic vesicle pool located at the active zone. B represents a synapse undergoing evoked activity. Pathway 1 operates at low frequency and route 2–3 is recruited under high-frequency stimulation. Synaptic vesicle membrane is retrieved by clathrin-dyna- min-mediated endocytosis directly from the plasma membrane adjacent to active zones in one step (step 1), or from deep plasma membrane invaginations or cisternae (step 2). These cisternae are also capable of sorting vesicle proteins into clathrin-dynamin-mediated budding profiles (step 2). Plasma-membrane-connected in- vaginations (step 2) give rise to endosomes (step 3) where membrane proteins get packed into different synaptic vesicle pools located at the active zone. Vesicle colors indicate different vesicular composition. Multivesicular body (MVB) accommodates targeting of presynaptic proteins to cell body lysosomes/degradative organelles as suggested by recent studies (Uytterhoeven et al. 2011; Maday et al. 2012).

after electrical stimulation is reversed by resting cle retrieval directly from the plasma membrane the nerve terminal, a process that occurs at the after vesicle fusion. If vesicles do not collapse expense of cisternae. These observations led to a into the plasma membrane, rapid reversal is model in which cisternae are the precursor or- achieved by the closure of transient opening ganelles of synaptic vesicles (Heuser and Reese pore. Such a mechanism is designated “kiss- 1973). The observation that clathrin-coated pits and-run” (Fesce et al. 1994). Alternatively, vesi- and vesicles are frequently observed budding cles may fully collapse into the plasma mem- from cisternae supports a model in which endo- brane and then be rapidly retrieved by cla- somes are intermediaries in vesicle recycling thrin-mediated endocytosis (Fig. 1B, step 1). (Fig. 1B, steps 2 and 3) (Heuser and Reese The speed and/or low frequencyof these retriev- 1973; Miller and Heuser 1984). In contrast, Cec- al events would make them difficult to identify carelli’s terminals were stimulated at low fre- by transmission electron microscopy. In this quency (2 Hz for up to 4 h), a key difference process, synaptic vesicle recycling could involve between these studies (Ceccarelli et al. 1973). a single vesicle budding step mediated by cla- Ceccarelli observed minimal modification in thrin, bypassing the need for an endosome in- the number of synaptic vesicles and an absence termediary (Takei et al. 1996; Granseth et al. of cisternae and coated membranes even though 2006). Thus, nerve terminal endosomes may ap- extracellular tracer was captured into synaptic pear under high frequency electrical activity of a vesicles. Ceccarelli’s findings suggest rapid vesi- synapse rather than being preexisting and static

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Heterogeneous Synaptic Vesicles

organelles (Fig. 1B, step 3). Alternatively, endo- cluding a dilution of vesicle dye (Richards et al. somes may preexist, yet they are rather small in 2000, 2003). Two predictions of this model are size and numbers in resting synapses or under experimentally supported. First, FM1–43 dye low frequency activity, making them anatomi- accumulates in cisternae induced by high fre- cally difficult to distinguish from the pool of quency stimulation arguing against this com- synaptic vesicles (Fig. 1A, step 1). partment as a dye dilution stage (Richards et al. The main challenge to the participation of 2000, 2003). Second, synaptic vesicles can fuse endosomes in synaptic vesicle recycling comes homotypically in vitro and possibly in vivo (Shi- from measurements of the FM1–43 dye content mizu et al. 2003; Rizzoli et al. 2006; He et al. during the life cycle of a synaptic vesicle. The key 2009). The use of FM dyes to track vesicles in argument is that the amount of dye taken up per combinationwith powerful genetic tools in Dro- vesicle byendocytosis equalsthe amount of dye a sophila or the use of transmembrane proteins vesicle releases on exocytosis, thus internalized that selectively tag synaptic vesicle pools in ver- vesicles do not communicate with intermediate tebrate neurons is offering new insights into the endosomes where dye would be diluted during role of endosomes in synaptic vesicle retrieval. the recycling process (Murthy and Stevens 1998; Zenisek et al. 2000). This model rests on the fol- lowing assumptions. First, the model considers BIOCHEMICAL, FUNCTIONAL, that there is a pool of preexisting dye-free endo- AND GENETIC EVIDENCE FAVOR ENDOSOMES AS SYNAPTIC VESICLE somes at nerve terminals whose volume is large RECYCLING STATIONS enough to dilute any dye brought by incoming vesicles. Second, the model assumes that endo- The search for insight into the function, origin, somes are obligate intermediaries for all recy- and fate of an organelle often begins with its cling synaptic vesicles; and third, it considers isolation and characterization of its compo- all synaptic vesicles to be biochemically identical nents. This isthe case for synaptic vesicles, which and that FM1–43 labels all recycling vesicles. can be purified to a high degree (Carlson et al. Endosomes exist in vivo as determined by im- 1978; Wagner et al. 1978; Huttner et al. 1983; munoelectron microscopy and three-dimen- Craige et al. 2004). We have a detailed and stoi- sional electron microscopy reconstruction of chiometric understanding of synaptic vesicle neuromuscular junctions, as well as the Calyx composition as a result of quantitative organelle of Held synapse in rats (Wucherpfennig et al. proteomics. These studies indicate that synaptic 2003; Tenget al. 2007; Uytterhoeven et al. 2011; vesicles are enriched, or at least possess, a pleth- Korber et al. 2012). However, they are low in ora of molecules that are bona-fide endosome number and are dynamic structures that form resident proteins (Table1) (Takamoriet al. 2000, and disappear at either low or high frequency 2006; Burre and Volknandt2007, 2011). Some of stimulation (Tenget al. 2007). This dynamic be- these proteins are integral membrane proteins, havior is common to nonneuronal endosomes which concentrate in synaptic vesicles. Thus, we whose appearance in cells requires continuous can infer the existence of mechanisms actively supply of vesicular membrane from the cell sur- sorting these membrane cargoes into vesicles. face(Collinet et al. 2010; Scita and Di Fiore 2010; The list of endosome markers is extensive Zeigerer et al. 2012). In fact, the presence of syn- and includes rab GTPases from diverse types of aptic endosomes is sensitive to the Drosophila endosomes, endosomal v- and t-SNARES, en- dynamin mutant allele, shibire (Wucherpfennig dosome localized munc18/nsec1-like proteins, et al. 2003). Thus it is possible that, like in non- and late endosome-lysosome membrane pro- neuronal cells, endosomes form by homotypic teins (Table 1) (Chen et al. 1985; Antonin et al. fusion of incoming vesicles (Collinet et al. 2010; 2000; Balla et al. 2002; Guo et al. 2003; Muzerelle Scita and Di Fiore 2010; Zeigerer et al. 2012). In et al. 2003; Pan et al. 2005; Rizzoli et al. 2006; such a scenario FM1–43 dye concentration in Scheuberet al. 2006; Craige et al. 2008; Morrison vesicles and endosomes would be similar, pre- et al. 2008; Hoopmann et al. 2010; Pavlos et al.

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2010; Chan et al. 2011; Kang et al. 2011; Sato anism (de Hoop et al. 1994; Star et al. 2005). In et al. 2011; Uytterhoeven et al. 2011; Zlatic Drosophila, rab5 and PIP3, a rab5 effector, are et al. 2011; Raingo et al. 2012). Importantly, present in synaptic bouton organelles that by coats involved in vesicle biogenesis from endo- electron microscopy are distinct from synaptic somes, such as the cytosolic clathrin-binding vesicles and are suggestive of endosomes. These adaptors AP-1, ubiquitous AP-3, and neuronal endosomes are sensitive to the loss of rab5 and AP-3 complexes copurify with synaptic vesicles dynamin activity (Wucherpfennig et al. 2003). (Robinson 2004; Takamori et al. 2006; Newell- The dynamin sensitivity indicates that bouton Litwa et al. 2007; Gronborg et al. 2010) The endosomes are dynamically maintained by presence of these proteins in synaptic vesicles membrane inflow from the plasma membrane, suggests that endosomes and their vesicle bio- rather than existing as static organelles. Impor- genesis machineries could be intermediaries in tantly, a rab5 dominant negative mutant impairs vesicle cycling (Fig. 2). In fact, we will discuss synaptic vesicle recycling, affecting both the re- below how perturbation of some of these endo- lease and retrieval of vesicles (Wucherpfennig somal molecules can modify the structure and et al. 2003). These phenotypes correlate with composition of synaptic vesicles, and how some the appearance of large membranous organelles of these organelle modifications impact chemi- in terminals and impaired neurotransmission cal neurotransmission. because of decreased quantal content, a reflec- Rab5a localizes to nerve terminals, and its tion of the vesicle pool available to fuse with the overexpressionimpairs synaptic vesiclerecycling plasma membrane (Shimizu et al. 2003; Wu- in mammalian cells by an undetermined mech- cherpfennig et al. 2003). These rab5 phenotypes predict that molecules regulating rab5 or the cy-

AP-1 cle of other endosomal rab GTPases should also VAMP4 affect neurotransmission. One such factor was recently identified in a screen for defects in syn- Rab5 aptic transmission in Drosophila (Verstreken Rab7 Rab11 et al. 2009). A loss of function mutant of a neu- Rab22 ronal rab GTPase activating protein (GAP), Sky- Rab35-Sky walker(Sky),enhancesneuronaltransmissionby Cholesterol- facilitating endosomal trafficking of synaptic rich microdomain vesicles at Drosophila neuromuscular junction AP-3 boutons (Uytterhoeven et al. 2011). Skywalker BLOC-1/dysbindin VAMP7 resides in boutons and activates the GTPase ac- tivity of rab35, and to a lesser extent rab23, but Figure 2. Endosome-sorting mechanisms at the nerve not rab5 (Uytterhoeven et al. 2011). Skywalker terminal. The image depicts a presynaptic early endo- mutants increase the quantal content twofold, a some as those presented in step 3 in Figure 1A or phenomenon that is phenocopied by constitu- B. The proposed rab composition of the endosome tivelyactive rab5, rab23, or rab35 mutants. How- is highlighted in one endosome yet different rabs could define distinct endosome populations. The en- ever, genetic interactions are restricted to Sky- dosome depicts three budding profiles with their pro- walker and rab35 (Uytterhoeven et al. 2011). posed clathrin-adaptor-sorting mechanism, AP-1 These results suggest that rab5 and rab35 operate and AP-3-BLOC-1, and a cholesterol-rich microdo- in parallel pathways that modify neurotransmis- main-dependent-sorting mechanism. The v-SNAREs sion at the nerve terminal (Fig. 2). Rab regulat- VAMP4and VAMP7have been paired with adaptors ed-traffic at the nerve terminal is likely to be known to bind these SNAREs. The degree to which more complex because, in addition to constitu- these endosome-sorting mechanisms operate in di- verse functional statuses of a synapse, namely, resting tively active rab5 and rab35 pathways, constitu- synapses, synchronous versus asynchronous evoked tivelyactive rab7 and rab11 mutants also perturb released, and low- versus high-frequency stimulation synaptic transmission at the neuromuscular release, is discussed in the text. junction (Fig. 2). The results by Uytterhoeven

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raise several important questions. First, do indi- alternative retrieval routes in addition to AP-2- vidual synaptic vesicles and presynaptic endo- clathrin-dependent mechanisms. This proposi- somes carry multiple rabs or just one (Fig. 2)? tion is compatible with evidence indicating that Does a vesicle retain or exchange its rabs? Rab synaptic vesicle recycling can proceed even in the exchange is known as maturation, a process in absence of AP-2 (Gu et al. 2008; Kim and Ryan which thesame endosome membrane exchanges 2009a,b; Willox and Royle 2012). one rab GTPase, such as rab5, for another rab, TheadaptorcomplexesAP-1andAP-3local- such as rab7 (Huotari and Helenius 2011). How ize to nerve terminals and copurify with synaptic does nerve terminal activity regulate rab-medi- vesicles, suggesting that these complexes partic- ated membrane fusion? An interesting possibil- ipate in their life cycle (Salazar et al. 2005; Seong ity isthattetanicstimulation,suchastheonethat et al. 2005; Takamori et al. 2006; Newell-Litwa induces the appearance of endosomes in nerve et al. 2009; Glyvuk et al. 2010; Gronborg et al. terminals, may favor homotypic fusion of vesi- 2010; Newell-Litwa et al. 2010). Moreover, AP-3 cles just originated from the plasma membrane, decorates synaptic vesicles by immunoelectron therefore carrying extracellular tracers, rather microscopy (Newman et al. 1995; Newell-Litwa than heterotypic fusion with the plasma mem- etal.2010).Predictably,AP-1andAP-3nullmice brane. The presence of multiple rabs in synaptic are characterized byone or more of the following vesicles and the phenotypes associated with rab phenotypes: alterations in synaptic vesicle size, function perturbation suggest that in addition composition or acidification; impaired intrater- tothemultiplemolecularlydistinctsynaptic ves- minal trafficking of neurotransmitter transport- icle pools, multiple recycling/sorting pathways ers;anddefectiveneurotransmission(Blumstein may also exist in the nerve terminal. et al. 2001; Nakatsu et al. 2004;Salazaret al. 2004; Seong et al. 2005; Voglmaier et al. 2006; Newell- Litwa et al. 2009, 2010; Glyvuk et al. 2010). AP-3 MOLECULARLY HETEROGENOUS functions in the generation of vesicles that un- SYNAPTIC VESICLES REQUIRE DIVERSE dergo spontaneous fusion, as well as in the gen- SORTING MACHINERIES eration of synaptic vesicles from activity-depen- Different coats assemble molecularly distinct dent bulk endocytosis-generated endosomes, vesicles (Bonifacino and Glick 2004; Faini et but not from the plasma membrane (Fig. 1A al. 2013). Among these coats, clathrin binding and B, step 3 and Fig. 2) (Scheuber et al. 2006; adaptors participate in sort- Cheung and Cousin 2012). AP-1 also partici- ing and vesicle budding events in compartments pates in the generation of synaptic vesicles relevant to the nerve terminal: endosomes and from activity-dependent bulk endocytosis-gen- the plasma membrane (Robinson 2004; Cana- erated endosomes in a pathway likely parallel to garajah et al. 2013). The adaptor complex AP-2 AP-3 (Fig. 1B, step 3 and Fig. 2) (Cheung and sorts membrane proteins into vesicle buds that Cousin 2012). An intriguing possibility is that pinch off at the plasma membrane, whereas the vSNAREs and adaptor pairs could define molec- adaptors complexes 1 and 3 (AP-1 and AP-3) do ularly and functionally distinct synaptic vesicle so from endosomes (Robinson 2004; Newell- pools (Fig. 2). VAMP7 is targeted by AP-3 com- Litwa et al. 2007). AP-3 was the first non-AP-2 plexes by direct binding to AP-3 (Martinez-Arca adaptor identified with a possible role at the et al. 2003; Salazar et al. 2006; Newell-Litwa synapse (Newman et al. 1995; Faundez et al. et al. 2009, 2010; Kent et al. 2012) and could 1998; Kantheti et al. 1998). The function of define synaptic vesicles that undergo spontane- AP-2 at the nerve terminal has been the subject ous fusion or are derived from bulkendocytosis- of great, recent reviews (see, for example, Royle generated endosomes. VAMP4and AP-1 could and Lagnado 2010; Saheki and De Camilli define activity-dependent, asynchronously re- 2012). Thus, we focus here on sorting machinery leased vesicles because VAMP-4 directly binds distinct from AP-2. We propose that diverse to AP-1 (Peden et al. 2001; Ren et al. 2013). sorting mechanisms at the nerve terminal offer This model would predict that VAMP4 and

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VAMP7would enrich into distinct vesicle popu- 2006; Larimore and Faundez, submitted). Null lations at the nerve terminal (Fig. 1B, step 3, and alleles of BLOC-1 subunits alter synaptic vesicle Fig. 2). composition, suggesting that BLOC-1 partici- What is remarkable of AP-1 and AP-3 is that pates in synaptic vesicle retrieval at the nerve neuronal enriched isoforms of these adaptors terminal (Newell-Litwa et al. 2009, 2010; Lari- participate in synaptic vesicle formation (New- more et al. 2011). The precise role of BLOC-1 in ell-Litwa et al. 2007; Glyvuk et al. 2010). Genetic mammalian cells is not yet defined but it could defects in these neuronal subunits cause pro- work as an accessoryadaptor protein byvirtue of found neurological and behavioral phenotypes its binding to AP-3 or, in a nonexclusive mech- in mice (Nakatsu et al. 2004; Seong et al. 2005; anism, BLOC-1could target membrane proteins Newell-Litwa et al. 2009, 2010; Glyvuk et al. independent of AP-3, as it does in nonneuronal 2010). Mutations in the neuronal enriched iso- cells (Di Pietro et al. 2006; Setty et al. 2008; Lar- form of AP-1, encoded by the AP1S2, cause imore et al. 2011; Gokhale et al. 2012). BLOC-1 syndromic and nonsyndromic intellectual dis- binds SNAREs and regulates either SNAREs’ ability in humans (Tarpey et al. 2006; Saillour subcellular localization or content in nonneu- et al. 2007; Borcket al. 2008; Ballarati et al. 2012). ronal cells. Some of these SNAREs, such as Single copy loss or mutation of the neuronal VAMP7and syntaxin13, are present in synaptic AP-3 subunit (AP3B2) is associated with schiz- vesicles (Huang et al. 1999; Salazar et al. 2006; ophrenia and autism spectrum disorders (Gok- Ghianietal.2009;Newell-Litwaetal.2009,2010; hale et al. 2012; O’Roak et al. 2012). It is impor- Gokhale et al. 2012). A soluble syntaxin13 frag- tant to emphasize that, although a loss of local ment reduces synaptic vesicle retrieval by inhib- presynaptic function of these adaptors could ex- iting endosomal recycling (Hoopmann et al. plain disease and mouse phenotypes, AP-1 and 2010). Thus, it is interesting to speculate that AP-3 adaptor function in the cell body could some of the neurological phenotypes observed also contribute to them. In fact, impaired AP-1 in BLOC-1 deficient mice may result from im- or AP-3 activity prevents delivery of membrane paired targeting of syntaxin13 at nerve terminal proteins from the cell body to dendrites (AP-1), endosomes (Ghiani and Dell’Angelica 2011; axons, and presynaptic terminals (AP-3) (Dwyer Mullin et al. 2011). et al. 2001; Seong et al. 2005; Larimore et al. 2011; Farias et al. 2012). CONCLUSION AND FUTURE DIRECTIONS There are two additional mechanisms that may participate in synaptic vesicle protein sort- No single model can on its own account for ing at the nerve terminal. One requires the bio- most observations on endo- and exocytosis, genesis of lysosomes complex 1, BLOC-1, the how these processes are coupled, and how syn- other cholesterol-rich membranes rafts (Fig. aptic vesicle proteins are sorted and recycled. 2). Cholesterol-rich domains may contribute The complexity of these mechanisms is under- to synaptic vesicle protein segregation and, ulti- scored by their diversity in every synapse type mately,to sortingin endosomesassuggested bya throughout an array of functional and develop- cholesterol sensitive clustering of synaptic vesi- mental states. As we gain a greater understand- cle membrane proteins in endosomes (Hoop- ing of the molecular composition of synaptic mann et al. 2010). The BLOC-1 complex is a vesicles, we have also established new tools cytosolic octamer present in early endosomes with which to study the mechanisms underlying and involved in the targeting of selected mem- their recycling at synapses. Increasing evidence brane proteins from endosomes to lysosome-re- suggests that SNAREs, clathrin-adaptors, and lated organelles and synaptic vesicles (Ghiani rabs may define distinct synaptic vesicle popu- and Dell’Angelica 2011; Mullin et al. 2011). lations. Indeed, these proteins and, in particu- Two of its subunits, dysbindin and pallidin, are lar, SNAREs will be useful for biochemical, found in the presynaptic terminal as determined functional, and microscopic discrimination of by immunoelectron microscopy (Talbot et al. vesicles subpopulations. However, remaining

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Heterogeneous Synaptic Vesicles

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Presynaptic Membrane Retrieval and Endosome Biology: Defining Molecularly Heterogeneous Synaptic Vesicles

Jennifer R. Morgan, Heather Skye Comstra, Max Cohen and Victor Faundez

Cold Spring Harb Perspect Biol 2013; doi: 10.1101/cshperspect.a016915

Subject Collection Endocytosis

Endocytosis: Past, Present, and Future Imaging and Modeling the Dynamics of Sandra L. Schmid, Alexander Sorkin and Marino Clathrin-Mediated Endocytosis Zerial Marcel Mettlen and Gaudenz Danuser Rab Proteins and the Compartmentalization of the Endocytic Accessory Factors and Regulation of Endosomal System Clathrin-Mediated Endocytosis Angela Wandinger-Ness and Marino Zerial Christien J. Merrifield and Marko Kaksonen Cargo Sorting in the Endocytic Pathway: A Key The Complex Ultrastructure of the Endolysosomal Regulator of Cell Polarity and Tissue Dynamics System Suzanne Eaton and Fernando Martin-Belmonte Judith Klumperman and Graça Raposo Unconventional Functions for Clathrin, ESCRTs, The Biogenesis of Lysosomes and and Other Endocytic Regulators in the Lysosome-Related Organelles Cytoskeleton, Cell Cycle, Nucleus, and Beyond: J. Paul Luzio, Yvonne Hackmann, Nele M.G. Links to Human Disease Dieckmann, et al. Frances M. Brodsky, R. Thomas Sosa, Joel A. Ybe, et al. Endocytosis of Viruses and Bacteria Endocytosis, Signaling, and Beyond Pascale Cossart and Ari Helenius Pier Paolo Di Fiore and Mark von Zastrow Lysosomal Adaptation: How the Lysosome Clathrin-Independent Pathways of Endocytosis Responds to External Cues Satyajit Mayor, Robert G. Parton and Julie G. Carmine Settembre and Andrea Ballabio Donaldson Reciprocal Regulation of Endocytosis and The Role of Endocytosis during Morphogenetic Metabolism Signaling Costin N. Antonescu, Timothy E. McGraw and Marcos Gonzalez-Gaitan and Frank Jülicher Amira Klip Endocytosis and Autophagy: Exploitation or Role of Endosomes and Lysosomes in Human Cooperation? Disease Sharon A. Tooze, Adi Abada and Zvulun Elazar Frederick R. Maxfield

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