Synaptic Vesicle Retrieval Research Articles

Neurons Specialize in Presynaptic Autophagy: A Perspective to Ameliorate Neurodegeneration.

The efficient and prolonged neurotransmission is reliant on the coordinated action of numerous synaptic proteins in the presynaptic compartment that remodels synaptic vesicles for neurotransmitter packaging and facilitates their exocytosis. Once a cycle of neurotransmission is completed, membranes and associated proteins are endocytosed into the cytoplasm for recycling or degradation. Both exocytosis and endocytosis are closely regulated in a timely and spatially constrained manner. Recent research demonstrated the impact of dysfunctional synaptic vesicle retrieval in causing retrograde degeneration of midbrain neurons and has highlighted the importance of such endocytic proteins, including auxilin, synaptojanin1 (SJ1), and endophilin A (EndoA) in neurodegenerative diseases. Additionally, the role of other associated proteins, including leucine-rich repeat kinase 2 (LRRK2), adaptor proteins, and retromer proteins, is being investigated for their roles in regulating synaptic vesicle recycling. Research suggests that the degradation of defective vesicles via presynaptic autophagy, followed by their recycling, not only revitalizes them in the active zone but also contributes to strengthening synaptic plasticity. The presynaptic autophagy rejuvenating terminals and maintaining neuroplasticity is unique in autophagosome formation. It involves several synaptic proteins to support autophagosome construction in tiny compartments and their retrograde trafficking toward the cell bodies. Despite having a comprehensive understanding of ATG proteins in autophagy, we still lack a framework to explain how autophagy is triggered and potentiated in compact presynaptic compartments. Here, we reviewed synaptic proteins' involvement in forming presynaptic autophagosomes and in retrograde trafficking of terminal cargos. The review also discusses the status of endocytic proteins and endocytosis-regulating proteins in neurodegenerative diseases and strategies to combat neurodegeneration.

Role of adaptor protein complexes in generating functionally distinct synaptic vesicle pools.

The synaptic vesicle (SV) cycle ensures the release of neurotransmitters and the replenishment of SVs to sustain neuronal activity. Multiple endocytosis and sorting pathways contribute to the recapture of the SV membrane and proteins after fusion. Adaptor protein (AP) complexes are among the critical components of the SV retrieval machinery. The canonical clathrin adaptor AP2 ensures the replenishment of most SVs across many neuronal populations. An alternative AP1/AP3-dependent process mediates the formation of a subset of SVs that differ from AP2 vesicles in molecular composition and respond preferentially during higher frequency firing. Furthermore, recent studies show that vesicular transporters for different neurotransmitters depend to a different extent on the AP3 pathway and this affects the release properties of the respective neurotransmitters. This review focuses on the current understanding of the AP-dependent molecular and functional diversity among SVs. We also discuss the contribution of these pathways to the regulation of neurotransmitter release across neuronal populations.

Phospholipid Scramblase 1 Controls Efficient Neurotransmission and Synaptic Vesicle Retrieval at Cerebellar Synapses.

Phospholipids (PLs) are asymmetrically distributed at the plasma membrane. This asymmetric lipid distribution is transiently altered during calcium-regulated exocytosis, but the impact of this transient remodeling on presynaptic function is currently unknown. As phospholipid scramblase 1 (PLSCR1) randomizes PL distribution between the two leaflets of the plasma membrane in response to calcium activation, we set out to determine its role in neurotransmission. We report here that PLSCR1 is expressed in cerebellar granule cells (GrCs) and that PLSCR1-dependent phosphatidylserine egress occurred at synapses in response to neuron stimulation. Synaptic transmission is impaired at GrC Plscr1 -/- synapses, and both PS egress and synaptic vesicle (SV) endocytosis are inhibited in Plscr1 -/- cultured neurons from male and female mice, demonstrating that PLSCR1 controls PL asymmetry remodeling and SV retrieval following neurotransmitter release. Altogether, our data reveal a novel key role for PLSCR1 in SV recycling and provide the first evidence that PL scrambling at the plasma membrane is a prerequisite for optimal presynaptic performance.

Chloroquine Affects Frequency-Dependent Endocytosis in Diaphragm Muscle of Old Mice

Chloroquine is an antimalarial agent commonly used as an autophagy inhibitor by preventing autolysosomal fusion. Autophagy is an important cellular process through which defective cytoplasmic structures are recycled and degraded that has been implicated in aging neuromuscular effects. We recently showed that acute chloroquine treatment blunts the maximal forces generated by the diaphragm muscle, likely by impairing neuromuscular transmission generally consistent with aging effects in the diaphragm muscle. In addition, old mice show increased accumulation of autophagy proteins in phrenic motor neurons, consistent with impaired autophagy flux. In the present study, we hypothesized that chloroquine treatment results in accumulation of bulk endosomes pre-synaptically. Each hemidiaphragm with attached phrenic nerve was excised from 24-month-old male and female C57BL/6 mice to evaluate frequency dependent (0 vs 80 Hz stimulation) uptake of the styryl dye FM4-64, given that 80-Hz stimulation frequency induces bulk endocytosis after synaptic vesicle retrieval. Diaphragm-phrenic nerve preparations were incubated in 5 μM FM4-64 for 1 h prior to 6-min nerve stimulation (0.5 ms supramaximal pulses in 80 Hz, 200 ms trains delivered at 40% duty cycle) followed by a 5-min post-stimulation incubation. FM4-64 uptake at diaphragm neuromuscular junctions (NMJs) was measured using confocal microscopy. Preparations were randomly assigned to co-incubation with chloroquine (50 μM) or vehicle (Rees-Simpson solution). There was minimal FM4-64 uptake in the absence of phrenic nerve stimulation, consistent with the activity-dependent uptake of the styryl dye. With 80 Hz stimulation, high levels of FM4-64 uptake were evident in both the chloroquine and vehicle-treated groups without significant differences across groups. FM4-64 fluorescence was evident throughout the presynpatic terminal with few areas of dense accumulation, consistent with retention of endosomes. There was no evidence of greater endosome accumulation with chloroquine treatment. Of note, a slight increase in FM4-64 uptake was evident in the chloroquine treated groups compared to vehicle in the non-stimulated NMJs. These results are consistent with FM4-64 uptake reflecting bulk endocytosis that mainly occurs during high frequency stimulation. The impairment in autophagy flux following chloroquine treatment is expected to result in endosome accumulation but it is possible that the stimulation protocol was insuffcient to elucidate this possibility. Collectively, the findings of this study are consistent with impaired autophagy at diaphragm presynaptic terminals which may underlie neuromuscular deficits observed in old age. Supported by NIH grant R01 AG057052 and the Mayo Clinic. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation.

Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, the glucose level in the brain plummets, forcing neurons to utilize alternative fuels. However, the molecular mechanisms of neuronal metabolic plasticity remain poorly understood. Here, we demonstrate that glucose-deprived neurons activate the CREB and PGC1α transcriptional program, which induces expression of the mitochondrial deacetylase Sirtuin 3 (Sirt3) both in vitro and in vivo. We show that Sirt3 localizes to axonal mitochondria and stimulates mitochondrial oxidative capacity in hippocampal nerve terminals. Sirt3 plays an essential role in sustaining synaptic transmission in the absence of glucose by providing metabolic support for the retrieval of synaptic vesicles after release. These results demonstrate that the transcriptional induction of Sirt3 facilitates the metabolic plasticity of synaptic transmission.

Observing single dynamin-mediated fission events in TIRFM-amenable synapses.

The presynapse features a unique tight coupling of exo- and endocytosis resulting in the formation of synaptic vesicles with uniform morphology. The difficulty in accessing the presynapse has hampered attempts to directly visualize the functionality of presynaptic proteins which enable such exquisite pairing. To this end our lab has developed “Xenapses”, TIRFM-able synapses, formed by mouse hippocampal neurons cultured on micropatterned host substrates coated with synaptogenic proteins. Xenapses show all the characteristics of a synapse and allow us to directly observe the behavior of proteins involved in compensatory endocytosis. Xenapses lend themselves to unroofing, revealing via SEM the membrane surface to be decorated with preassembled clathrin structures, concomitant with a pre-sorted and pre-assembled readily retrievable pool (RRetP) of endocytic structures. We have further combined this preparation with CRISPR-Cas9 to endogenously label dynamin I. This has enabled the study of triggered compensatory endocytosis at an unprecedented spatial and temporal resolution. Dynamin-dependent fission occurred as discreet, quantal events, demonstrating the rate of endocytosis to be determined by the number of vesicles retrieved within a unit of time rather than by an intrinsic value. While dynamin was recruited within subsecond timescale following a single action potential, the subsequent assembly and fission, denoted by gradual increase in fluorescence followed by rapid collapse, occurred over many seconds with a peak at 5 seconds at physiological temperature. This casts a shadow over the dynamin-dependent ultrafast endocytic mode proposed to predominate under such conditions. These observations advance dynamin fission as the rate-limiting step in endocytosis, with the preassembled RRetP providing an element of speed advantage for the rapid, high fidelity retrieval of synaptic vesicles. The full potential of our system will be realized by investigating the choreography of the key endocytic proteins relative to dynamin fission.

Postsynaptic Neuroligin-1 Mediates Presynaptic Endocytosis During Neuronal Activity.

Fast, high-fidelity neurotransmission and synaptic efficacy requires tightly regulated coordination of pre- and postsynaptic compartments and alignment of presynaptic release sites with postsynaptic receptor nanodomains. Neuroligin-1 (Nlgn1) is a postsynaptic cell-adhesion protein exclusively localised to excitatory synapses that is crucial for coordinating the transsynaptic alignment of presynaptic release sites with postsynaptic AMPA receptors as well as postsynaptic transmission and plasticity. However, little is understood about whether the postsynaptic machinery can mediate the molecular architecture and activity of the presynaptic nerve terminal, and thus it remains unclear whether there are presynaptic contributions to Nlgn1-dependent control of signalling and plasticity. Here, we employed a presynaptic reporter of neurotransmitter release and synaptic vesicle dynamics, synaptophysin-pHluorin (sypHy), to directly assess the presynaptic impact of loss of Nlgn1. We show that lack of Nlgn1 had no effect on the size of the readily releasable or entire recycling pool of synaptic vesicles, nor did it impact exocytosis. However, we observed significant changes in the retrieval of synaptic vesicles by compensatory endocytosis, specifically during activity. Our data extends growing evidence that synaptic adhesion molecules critical for forming transsynaptic scaffolds are also important for regulating activity-induced endocytosis at the presynapse.

Monitoring Activity-Dependent Bulk Endocytosis in Primary Neuronal Culture Using Large Fluorescent Dextrans.

The efficient recycling of synaptic vesicles (SVs) during neuronal activity is central for sustaining brain function. During intense neuronal activity, the dominant mechanism of SV retrieval is activity-dependent bulk endocytosis (ADBE). Here, we describe a method to monitor ADBE in isolation from other SV endocytosis modes, via the uptake of large fluorescent fluid-phase markers in primary neuronal culture. Furthermore, we outline how to monitor ADBE using this approach across a field of neurons or in individual neurons.

PICK1 Controls Activity-Dependent Synaptic Vesicle Cargo Retrieval

Efficient retrieval of synaptic vesicles (SVs) is crucial to sustain synaptic transmission. Protein interacting with C-kinase 1 (PICK1) is a unique PDZ (postsynaptic density-95/disc-large/zona-occluden-1)- and BAR (Bin-Amphiphysin-Rvs )-domain-containing protein that regulates the trafficking of postsynaptic glutamate receptors. It is also expressed in presynaptic terminals and is associated with the SVs; however, its role in regulating SV recycling remains unknown. Here, we show that PICK1 loss of function selectively slows the kinetics of SV endocytosis in primary hippocampal neurons during high-frequency stimulation. PICK1 knockdown also causes surface stranding and mislocalization of major SV proteins, synaptophysin and vGlut1, along the axon. A functional PDZ domain of PICK1 and its interaction with the core endocytic adaptor protein (AP)-2 are required for the proper targeting and clustering of synaptophysin. Furthermore, PICK1 and its interaction with AP-2 are required for efficient SV endocytosis and sustained glutamate release. Our findings, therefore, identify PICK1 as a key regulator of presynaptic vesicle recycling in central synapses.

Presynaptic dysfunction in neurodevelopmental disorders: Insights from the synaptic vesicle life cycle.

The activity-dependent fusion, retrieval and recycling of synaptic vesicles is essential for the maintenance of neurotransmission. Until relatively recently it was believed that most mutations in genes that were essential for this process would be incompatible with life, because of this fundamental role. However, an ever-expanding number of mutations in this very cohort of genes are being identified in individuals with neurodevelopmental disorders, including autism, intellectual disability and epilepsy. This article will summarize the current state of knowledge linking mutations in presynaptic genes to neurodevelopmental disorders by sequentially covering the various stages of the synaptic vesicle life cycle. It will also discuss how perturbations of specific stages within this recycling process could translate into human disease. Finally, it will also provide perspectives on the potential for future therapy that are targeted to presynaptic function.

Activity and Cytosolic Na+ Regulate Synaptic Vesicle Endocytosis

Retrieval of synaptic vesicles via endocytosis is essential for maintaining sustained synaptic transmission, especially for neurons that fire action potentials at high frequencies. However, how neuronal activity regulates synaptic vesicle recycling is largely unknown. Here we report that Na+ substantially accumulated in the mouse calyx of Held terminals of either sex during repetitive high-frequency spiking. Elevated presynaptic Na+ accelerated both slow and rapid forms of endocytosis and facilitated endocytosis overshoot, but did not affect the readily releasable pool size, Ca2+ influx, or exocytosis. To examine whether this facilitation of endocytosis is related to the Na+-dependent vesicular content change, we dialyzed glutamate into the presynaptic cytosol or blocked the vesicular glutamate uptake with bafilomycin and found that the rate of endocytosis was not affected by regulating the vesicular glutamate content. Endocytosis is critically dependent on intracellular Ca2+, and the activity of Na+/Ca2+ exchanger (NCX) may be altered when the Na+ gradient is changed. However, neither NCX inhibitor nor change of extracellular Na+ concentration affected the endocytosis rate. Moreover, two-photon Ca2+ imaging showed that presynaptic Na+ did not affect the action potential-evoked intracellular Ca2+ transient and decay. Therefore, we revealed a novel mechanism of cytosolic Na+ in accelerating vesicle endocytosis. During high-frequency synaptic transmission, when large numbers of synaptic vesicles were fused, the rapid buildup of presynaptic cytosolic Na+ promoted vesicle recycling and sustained synaptic transmission.SIGNIFICANCE STATEMENT High-frequency firing neurons are widely distributed in the CNS. A large number of synaptic vesicles are released during high-frequency synaptic transmission; accordingly, synaptic vesicles need to be recycled rapidly to replenish the vesicle pool. Synaptic vesicle exocytosis and endocytosis are tightly coupled, and their coupling is essential for synaptic function and structural stability. We showed here that intracellular Na+ concentration at the calyx of Held terminal increased rapidly during spike activity and the increased Na+ accelerated endocytosis. Thus, when large numbers of synaptic vesicles are released during high-frequency synaptic transmission, Na+ accumulated in terminals and facilitated vesicle recycling. These findings represent a novel cellular mechanism that supports reliable synaptic transmission at high frequency in the CNS.

VAMP4 Maintains a Ca2+-Sensitive Pool of Spontaneously Recycling Synaptic Vesicles.

Spontaneous neurotransmitter release is a fundamental property of synapses in which neurotransmitter filled vesicles release their content independent of presynaptic action potentials (APs). Despite their seemingly random nature, these spontaneous fusion events can be regulated by Ca2+ signaling pathways. Here, we probed the mechanisms that maintain Ca2+ sensitivity of spontaneous release events in synapses formed between hippocampal neurons cultured from rats of both sexes. In this setting, we examined the potential role of vesicle-associated membrane protein 4 (VAMP4), a vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein in spontaneous neurotransmission. Our results show that VAMP4 is required for Ca2+-dependent spontaneous excitatory neurotransmission, with a limited role in spontaneous inhibitory neurotransmission. Key residues in VAMP4 that regulate its retrieval as well as functional clathrin-mediated vesicle trafficking were essential for the maintenance of VAMP4-mediated spontaneous release. Moreover, high-frequency stimulation (HFS) that typically triggers asynchronous release and retrieval of VAMP4 from the plasma membrane also augmentsCa2+-sensitive spontaneous release for up to 30 min in a VAMP4-dependent manner. This VAMP4-mediated link between asynchronous and spontaneous excitatory neurotransmission might serve as a presynaptic substrate for synaptic plasticity coupling distinct forms of release.SIGNIFICANCE STATEMENT Spontaneous neurotransmitter release that occurs independent of presynaptic action potentials (APs) shows significant sensitivity to intracellular Ca2+ levels. In this study, we identify the vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) molecule vesicle-associated membrane protein 4 (VAMP4) as a key component of the machinery that maintains these Ca2+-sensitive fraction of spontaneous release events. Following brief intense activity, VAMP4-dependent synaptic vesicle retrieval supports a pool of vesicles that fuse spontaneously in the long term. We propose that this vesicle trafficking pathway acts to shape spontaneous release and associated signaling based on previous activity history of synapses.

Programmable pH-Responsive DNA Nanosensors for Imaging Exocytosis and Retrieval of Synaptic Vesicles.

Exocytosis and retrieval of synaptic vesicles (SVs) are vital steps during neurotransmitter propagation between neurons. Visualization of this dynamics of SVs is significant for elucidating the mechanisms underlying synaptic transmission but remains challenging without an efficient, reliable, and biocompatible labeling method. In this work, we developed pH-responsive ratiometric DNA tetrahedral nanoprobes (pHadtnps) that could specifically label recycling SVs with high stability and effective background suppression. On the basis of the luminal pH alternation during the recycling of SVs, pHadtnps were able to illustrate their exocytosis and retrieval in real time. Moreover, with the high programmability of DNA nanotechnology, these nanoprobes could be flexibly equipped with different functional moieties, holding great promise for developing various versatile tools for studying communication in neuronal networks.

Is Ca2+ Essential for Synaptic Vesicle Endocytosis?

Synaptic vesicle fusion is coupled to swift retrieval of vesicle components from the synaptic plasma membrane. Ca2+ has been assumed to be a key mediator of this coupling. In a recent study, Orlando et al. unequivocally demonstrate that Ca2+ is not essential for synaptic vesicle retrieval.

PICK1 Controls Activity-Dependent Synaptic Vesicle Cargo Retrieval

Efficient retrieval of synaptic vesicles (SVs) is crucial to sustain synaptic transmission. PICK1 is a unique PDZ- and BAR-domain-containing protein that regulates the trafficking of postsynaptic glutamate receptors. It is also expressed in presynaptic terminals and is associated with the SVs; however, its role in regulating SV recycling remains unknown. Here we show that PICK1 loss of function selectively slows the kinetics of SV endocytosis in primary hippocampal neurons during high-frequency stimulation. PICK1 knockdown also causes surface stranding and mislocalization of the major SV protein synaptophysin along the axon. A functional PDZ domain of PICK1 and its interaction with the core endocytic protein AP-2 are required for the proper targeting and clustering of synaptophysin. We further show that PICK1, and its interaction with AP-2, are required for efficient SV endocytosis and sustained glutamate release. Our findings therefore identify PICK1 as a key regulator of presynaptic vesicle recycling in central synapses.

Visualization of Synchronous or Asynchronous Release of Single Synaptic Vesicle in Active-Zone-Like Membrane Formed on Neuroligin-Coated Glass Surface.

Fast repetitive synaptic transmission depends on efficient exocytosis and retrieval of synaptic vesicles around a presynaptic active zone. However, the functional organization of an active zone and regulatory mechanisms of exocytosis, endocytosis and reconstruction of release-competent synaptic vesicles have not been fully elucidated. By developing a novel visualization method, we attempted to identify the location of exocytosis of a single synaptic vesicle within an active zone and examined movement of synaptic vesicle protein synaptophysin (Syp) after exocytosis. Using cultured hippocampal neurons, we induced formation of active-zone-like membranes (AZLMs) directly adjacent and parallel to a glass surface coated with neuroligin, and imaged Syp fused to super-ecliptic pHluorin (Syp-SEP) after its translocation to the plasma membrane from a synaptic vesicle using total internal reflection fluorescence microscopy (TIRFM). An AZLM showed characteristic molecular and functional properties of a presynaptic active zone. It contained active zone proteins, cytomatrix at the active zone-associated structural protein (CAST), Bassoon, Piccolo, Munc13 and RIM, and showed an increase in intracellular Ca2+ concentration upon electrical stimulation. In addition, single-pulse stimulation sometimes induced a transient increase of Syp-SEP signal followed by lateral spread in an AZLM, which was considered to reflect an exocytosis event of a single synaptic vesicle. The diffusion coefficient of Syp-SEP on the presynaptic plasma membrane after the membrane fusion was estimated to be 0.17–0.19 μm2/s, suggesting that Syp-SEP diffused without significant obstruction. Synchronous exocytosis just after the electrical stimulation tended to occur at multiple restricted sites within an AZLM, whereas locations of asynchronous release occurring later after the stimulation tended to be more scattered.

APache Is an AP2-Interacting Protein Involved in Synaptic Vesicle Trafficking and Neuronal Development

Synaptic transmission is critically dependent on synaptic vesicle (SV) recycling. Although the precise mechanisms of SV retrieval are still debated, it is widely accepted that a fundamental role is played by clathrin-mediated endocytosis, a form of endocytosis that capitalizes on the clathrin/adaptor protein complex 2 (AP2) coat and several accessory factors. Here, we show that the previously uncharacterized protein KIAA1107, predicted by bioinformatics analysis to be involved in the SV cycle, is an AP2-interacting clathrin-endocytosis protein (APache). We found that APache is highly enriched in the CNS and is associated with clathrin-coated vesicles via interaction with AP2. APache-silenced neurons exhibit a severe impairment of maturation at early developmental stages, reduced SV density, enlarged endosome-like structures, and defects in synaptic transmission, consistent with an impaired clathrin/AP2-mediated SV recycling. Our data implicate APache as an actor in the complex regulation of SVtrafficking, neuronal development, and synaptic plasticity.

Stimulation of synapse formation between stem cell-derived neurons and native brainstem auditory neurons

Integration of stem cell-derived cells into native cellular environment remains a challenge in the field. This study developed novel methods to co-culture neural stem cell-derived spiral ganglion-like neurons (ScNs) and mouse auditory cochlear nucleus (CN) neurons to understand whether ScNs of the peripheral nervous system (PNS) synapse with CN neurons of the central nervous system (CNS). ScNs were obtained from neural stem cells that were derived from transgenic mouse pre-labeled with enhanced green fluorescent protein (EGFP), whereas CN neurons were from postnatal mouse primary cultures. ScNs and CN neurons were co-cultured for 4–6 days in the absence or presence of astrocyte-conditioned medium (ACM). Class III β-tubulin (TUJ1)-expressing connections were found between ScNs and CN neurons. Expression of the synaptic vesicle marker SV2 was significantly increased along connections between ScNs and CN neurons in the presence of ACM. Immunodepletion and knockout studies indicated that thrombospodin-1 played an important role in ACM-exerted synaptogenic effects. Newly-generated synapse-like structures expressed glutamatergic marker VGluT1, pre- and post-synaptic proteins. Synaptic vesicle recycling studies suggested functional synaptic vesicle retrieval. These results reveal that stem cell-derived PNS neurons are able to form functional connections with native CNS neurons, which is critical for stem cell-based neural pathway regeneration.

Integration of Synaptic Vesicle Cargo Retrieval with Endocytosis at Central Nerve Terminals.

Central nerve terminals contain a limited number of synaptic vesicles (SVs) which mediate the essential process of neurotransmitter release during their activity-dependent fusion. The rapid and accurate formation of new SVs with the appropriate cargo is essential to maintain neurotransmission in mammalian brain. Generating SVs containing the correct SV cargo with the appropriate stoichiometry is a significant challenge, especially when multiple modes of endocytosis exist in central nerve terminals, which occur at different locations within the nerve terminals. These endocytosis modes include ultrafast endocytosis, clathrin-mediated endocytosis (CME) and activity-dependent bulk endocytosis (ADBE) which are triggered by specific patterns of neuronal activity. This review article will assess the evidence for the role of classical adaptor protein complexes in SV retrieval, discuss the role of monomeric adaptors and how interactions between specific SV cargoes can facilitate retrieval. In addition it will consider the evidence for preassembled plasma membrane cargo complexes and their role in facilitating these endocytosis modes. Finally it will present a unifying model for cargo retrieval at the presynapse, which integrates endocytosis modes in time and space.

Synapses in neurodegenerative diseases.

Synapse is the basic structural and functional component for neural communication in the brain. The presynaptic terminal is the structural and functionally essential area that initiates communication and maintains the continuous functional neural information flow. It contains synaptic vesicles (SV) filled with neurotransmitters, an active zone for release, and numerous proteins for SV fusion and retrieval. The structural and functional synaptic plasticity is a representative characteristic; however, it is highly vulnerable to various pathological conditions. In fact, synaptic alteration is thought to be central to neural disease processes. In particular, the alteration of the structural and functional phenotype of the presynaptic terminal is a highly significant evidence for neural diseases. In this review, we specifically describe structural and functional alteration of nerve terminals in several neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD).