synaptic vesicle release
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eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Chad W Sauvola ◽  
Yulia Akbergenova ◽  
Karen L Cunningham ◽  
Nicole A Aponte-Santiago ◽  
J Troy Littleton

Synaptic vesicle release probability (Pr) is a key presynaptic determinant of synaptic strength established by cell intrinsic properties and further refined by plasticity. To characterize mechanisms that generate Pr heterogeneity between distinct neuronal populations, we examined glutamatergic tonic (Ib) and phasic (Is) motoneurons in Drosophila with stereotyped differences in Pr and synaptic plasticity. We found the decoy SNARE Tomosyn is differentially expressed between these motoneuron subclasses and contributes to intrinsic differences in their synaptic output. Tomosyn expression enables tonic release in Ib motoneurons by reducing SNARE complex formation and suppressing Pr to generate decreased levels of synaptic vesicle fusion and enhanced resistance to synaptic fatigue. In contrast, phasic release dominates when Tomosyn expression is low, enabling high intrinsic Pr at Is terminals at the expense of sustained release and robust presynaptic potentiation. In addition, loss of Tomosyn disrupts the ability of tonic synapses to undergo presynaptic homeostatic potentiation (PHP).


eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Catia AP Silva ◽  
Annik Yalnizyan-Carson ◽  
M Victoria Fernández Busch ◽  
Mike van Zwieten ◽  
Matthijs Verhage ◽  
...  

Developing neurons form synapses at a high rate. Synaptic transmission is very energy-demanding and likely requires ATP production by mitochondria nearby. Mitochondria might be targeted to active synapses in young dendrites, but whether such motility regulation mechanisms exist is unclear. We investigated the relationship between mitochondrial motility and neuronal activity in the primary visual cortex of young mice in vivo and in slice cultures. During the first 2 postnatal weeks, mitochondrial motility decreases while the frequency of neuronal activity increases. Global calcium transients do not affect mitochondrial motility. However, individual synaptic transmission events precede local mitochondrial arrest. Pharmacological stimulation of synaptic vesicle release, but not focal glutamate application alone, stops mitochondria, suggesting that an unidentified factor co-released with glutamate is required for mitochondrial arrest. A computational model of synaptic transmission-mediated mitochondrial arrest shows that the developmental increase in synapse number and transmission frequency can contribute substantially to the age-dependent decrease of mitochondrial motility.


Author(s):  
Emily Miyoshi ◽  
Tina Bilousova ◽  
Mikhail Melnik ◽  
Danyl Fakhrutdinov ◽  
Wayne W. Poon ◽  
...  

AbstractSynaptic transfer of tau has long been hypothesized from the human pathology pattern and has been demonstrated in vitro and in vivo, but the precise mechanisms remain unclear. Extracellular vesicles such as exosomes have been suggested as a mechanism, but not all tau is exosomal. The present experiments use a novel flow cytometry assay to quantify depolarization of synaptosomes by KCl after loading with FM2–10, which induces a fluorescence reduction associated with synaptic vesicle release; the degree of reduction in cryopreserved human samples equaled that seen in fresh mouse synaptosomes. Depolarization induced the release of vesicles in the size range of exosomes, along with tetraspanin markers of extracellular vesicles. A number of tau peptides were released, including tau oligomers; released tau was primarily unphosphorylated and C-terminal truncated, with Aβ release just above background. When exosomes were immunopurified from release supernatants, a prominent tau band showed a dark smeared appearance of SDS-stable oligomers along with the exosomal marker syntenin-1, and these exosomes induced aggregation in the HEK tau biosensor assay. However, the flow-through did not seed aggregation. Size exclusion chromatography of purified released exosomes shows faint signals from tau in the same fractions that show a CD63 band, an exosomal size signal, and seeding activity. Crude synaptosomes from control, tauopathy, and AD cases demonstrated lower seeding in tauopathy compared to AD that is correlated with the measured Aβ42 level. These results show that AD synapses release exosomal tau that is C-terminal-truncated, oligomeric, and with seeding activity that is enhanced by Aβ. Taken together with previous findings, these results are consistent with a direct prion-like heterotypic seeding of tau by Aβ within synaptic terminals, with subsequent loading of aggregated tau onto exosomes that are released and competent for tau seeding activity.


2021 ◽  
Author(s):  
Chad W. Sauvola ◽  
Yulia Akbergenova ◽  
Karen L Cunningham ◽  
Nicole A. Aponte-Santiago ◽  
J. Troy Littleton

Synaptic vesicle release probability (Pr) is a key presynaptic determinant of synaptic strength established by cell intrinsic properties and further refined by plasticity. To characterize mechanisms that generate Pr heterogeneity between distinct neuronal populations, we examined glutamatergic tonic (Ib) and phasic (Is) motoneurons in Drosophila with stereotyped differences in Pr and synaptic plasticity. We found the decoy SNARE Tomosyn is differentially expressed between these motoneuron subclasses and contributes to intrinsic differences in their synaptic output. Tomosyn expression enables tonic release in Ib motoneurons by reducing SNARE complex formation and suppressing Pr to generate decreased levels of synaptic vesicle fusion and enhanced resistance to synaptic fatigue. In contrast, phasic release dominates when Tomosyn expression is low, enabling high intrinsic Pr at Is terminals at the expense of sustained release and robust presynaptic potentiation. In addition, loss of Tomosyn disrupts the ability of tonic synapses to undergo presynaptic homeostatic potentiation (PHP).


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Zoé Butti ◽  
Yingzhou Edward Pan ◽  
Jean Giacomotto ◽  
Shunmoogum A. Patten

AbstractThe most common genetic cause of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is a hexanucleotide repeat expansion within the C9orf72 gene. Reduced levels of C9orf72 mRNA and protein have been found in ALS/FTD patients, but the role of this protein in disease pathogenesis is still poorly understood. Here, we report the generation and characterization of a stable C9orf72 loss-of-function (LOF) model in the zebrafish. We show that reduced C9orf72 function leads to motor defects, muscle atrophy, motor neuron loss and mortality in early larval and adult stages. Analysis of the structure and function of the neuromuscular junctions (NMJs) of the larvae, reveal a marked reduction in the number of presynaptic and postsynaptic structures and an impaired release of quantal synaptic vesicles at the NMJ. Strikingly, we demonstrate a downregulation of SV2a upon C9orf72-LOF and a reduced rate of synaptic vesicle cycling. Furthermore, we show a reduced number and size of Rab3a-postive synaptic puncta at NMJs. Altogether, these results reveal a key function for C9orf72 in the control of presynaptic vesicle trafficking and release at the zebrafish larval NMJ. Our study demonstrates an important role for C9orf72 in ALS/FTD pathogenesis, where it regulates synaptic vesicle release and neuromuscular functions.


2021 ◽  
Author(s):  
Feng Chen ◽  
Yanting Chen ◽  
Huiyi Chen ◽  
Yongxiang Wang ◽  
Wenyan Wei ◽  
...  

Abstract Background: The ε4 allele of the Apolipoprotein E (APOE) gene is a major genetic risk determinant of sporadic Alzheimer's disease (AD). Its protein product APOE4 has been demonstrated to coffers deleterious effects for various neurodegenerative disorders related to cognitive impairment, including AD. A line of evidence implied that APOE4 affects these diseases partly through its synaptic damage. However, the mechanisms underlying this have not been fully interpreted.Methods: Proteomics analysis, Co-immunoprecipitation assay (Co-IP), Bimolecular fluorescence complementation (BIFC), and Proximity ligation assay (PLA) assays were used to screen and verify the interactome of APOE, which in an APOE4-priority manner. The molecular docking and molecular dynamic analysis were conducted to elucidate the molecular mechanisms that APOE3 differs from APOE4 in the binding ability of VAMP2. Adeno-associated virus expressing APOE3 and APOE4 was stereotaxically injected into the Hippocampus of Apoe-/- mice, and in vitro recombinant proteins experiments were conducted to verify the AOPE on soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assemble. FM4-64 fluorescent dye labeling assay was explored in hippocampus from APOE3-TR and APOE4-TR mice to study the APOE genotype effect on synaptic vesicle release.Results:Using proteomics analysis, we screened interactomes of APOE3 and APOE4 in neurons, respectively. Then, VAMP2 protein was selected for further analysis through related bioinformatics analysis. Via Co-IP, BIFC, and PLA assays,we demonstrated that APOE directly interacts with VAMP2 in an E4 > E3 manner in vitro and in vivo. The molecular docking and molecular dynamic analysis suggested that the APOE4-VAMP2 complex was more stable and had higher affinity than APOE3-VAMP2, may due to the increased contribution of hydrogen bonding, hamper VAMP2 to form the SNARE complex. The further in vitro and in vivo results suggest that APOE4 blocks the SNARE complex assembly, negatively regulating synaptic vesicle release, finally contributing to the synaptic damage and cognitive impairment.Conclusions:Our findings identify SNARE protein as an APOE interactor, and APOE4 isoform effects on SNARE complex formation, mediates APOE4-induced synaptic dysfunction. Our results provide insights into APOE4-mediated synapse toxicity, and suggested new avenues for specifically targeting early presynaptic dysfunction in AD.


2021 ◽  
Vol 7 (18) ◽  
pp. eabf3873
Author(s):  
Daniela Ivanova ◽  
Katharine L. Dobson ◽  
Akshada Gajbhiye ◽  
Elizabeth C. Davenport ◽  
Daniela Hacker ◽  
...  

Synaptic vesicle (SV) release probability (Pr), determines the steady state and plastic control of neurotransmitter release. However, how diversity in SV composition arises and regulates the Pr of individual SVs is not understood. We found that modulation of the copy number of the noncanonical vesicular SNARE (soluble N-ethylmaleimide–sensitive factor attachment protein receptor), vesicle-associated membrane protein 4 (VAMP4), on SVs is key for regulating Pr. Mechanistically, this is underpinned by its reduced ability to form an efficient SNARE complex with canonical plasma membrane SNAREs. VAMP4 has unusually high synaptic turnover and is selectively sorted to endolysosomes during activity-dependent bulk endocytosis. Disruption of endolysosomal trafficking and function markedly increased the abundance of VAMP4 in the SV pool and inhibited SV fusion. Together, our results unravel a new mechanism for generating SV heterogeneity and control of Pr through coupling of SV recycling to a major clearing system that regulates protein homeostasis.


2021 ◽  
Vol 118 (14) ◽  
pp. e2021770118
Author(s):  
Si-Yao Lu ◽  
Chong-Lei Fu ◽  
Liang Liang ◽  
Bo Yang ◽  
Wei Shen ◽  
...  

microRNA-218 (miR-218) has been linked to several cognition related neurodegenerative and neuropsychiatric disorders. However, whether miR-218 plays a direct role in cognitive functions remains unknown. Here, using the miR-218 knockout (KO) mouse model and the sponge/overexpression approaches, we showed that miR-218-2 but not miR-218-1 could bidirectionally regulate the contextual and spatial memory in the mice. Furthermore, miR-218-2 deficiency induced deficits in the morphology and presynaptic neurotransmitter release in the hippocampus to impair the long term potentiation. Combining the RNA sequencing analysis and luciferase reporter assay, we identified complement component 3 (C3) as a main target gene of miR-218 in the hippocampus to regulate the presynaptic functions. Finally, we showed that restoring the C3 activity in the miR-218-2 KO mice could rescue the synaptic and learning deficits. Therefore, miR-218-2 played an important role in the cognitive functions of mice through C3, which can be a mechanism for the defective cognition of miR-218 related neuronal disorders.


Author(s):  
Maria Andres-Alonso ◽  
Michael R. Kreutz ◽  
Anna Karpova

AbstractThe complex morphology of neurons, the specific requirements of synaptic neurotransmission and the accompanying metabolic demands create a unique challenge for proteostasis. The main machineries for neuronal protein synthesis and degradation are localized in the soma, while synaptic junctions are found at vast distances from the cell body. Sophisticated mechanisms must, therefore, ensure efficient delivery of newly synthesized proteins and removal of faulty proteins. These requirements are exacerbated at presynaptic sites, where the demands for protein turnover are especially high due to synaptic vesicle release and recycling that induces protein damage in an intricate molecular machinery, and where replacement of material is hampered by the extreme length of the axon. In this review, we will discuss the contribution of the two major pathways in place, autophagy and the endolysosomal system, to presynaptic protein turnover and presynaptic function. Although clearly different in their biogenesis, both pathways are characterized by cargo collection and transport into distinct membrane-bound organelles that eventually fuse with lysosomes for cargo degradation. We summarize the available evidence with regard to their degradative function, their regulation by presynaptic machinery and the cargo for each pathway. Finally, we will discuss the interplay of both pathways in neurons and very recent findings that suggest non-canonical functions of degradative organelles in synaptic signalling and plasticity.


2020 ◽  
Author(s):  
Evan R. Harrell ◽  
Diogo Pimentel ◽  
Gero Miesenböck

AbstractHomeostatic matching of pre- and postsynaptic function has been observed in many species and neural structures, but whether transcriptional changes contribute to this form of trans-synaptic coordination remains unknown. To identify genes whose expression is altered in presynaptic neurons as a result of perturbing postsynaptic excitability, we applied a transcriptomics-friendly, temperature-inducible Kir2.1-based activity clamp at the first synaptic relay of the Drosophila olfactory system, a central synapse known to exhibit trans-synaptic homeostatic matching. Twelve hours after adult-onset suppression of activity in postsynaptic antennal lobe projection neurons, we detected changes in the expression of many genes in the third antennal segment, which houses the somata of presynaptic olfactory receptor neurons. These changes affected genes with roles in synaptic vesicle release and synaptic remodeling, including several genes implicated in homeostatic plasticity at the neuromuscular junction. At 48 hours and beyond, the transcriptional landscape was tilted toward proteostasis, energy metabolism, and cellular stress defenses, indicating that the system had been pushed to its homeostatic limits. Our data provide insights into the nature of homeostatic compensation at a central synapse and identify many genes engaged in synaptic homeostasis. The presynaptic transcriptional response to genetically targeted postsynaptic perturbations could be exploited for the construction of novel connectivity tracing tools.Significance StatementHomeostatic feedback mechanisms adjust intrinsic and synaptic properties of neurons to keep their average activity levels constant. We show that, at a central synapse in the fruit fly brain, these mechanisms include changes in presynaptic gene expression that are instructed by an abrupt loss of postsynaptic excitability. The trans-synaptically regulated genes have roles in synaptic vesicle release and synapse remodeling; protein synthesis, folding, and degradation; and energy metabolism. Our analysis suggests that similar homeostatic machinery operates at peripheral and central synapses, identifies some of its components, and potentially opens new opportunities for the development of connectivity-based gene expression systems.


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