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Trends in Neurosciences Jun 2019Presynaptic boutons support neurotransmitter release with nanoscale precision at sub-millisecond timescales. Studies over the past two decades have revealed a rich... (Review)
Review
Presynaptic boutons support neurotransmitter release with nanoscale precision at sub-millisecond timescales. Studies over the past two decades have revealed a rich tapestry of molecular players governing synaptic vesicle fusion at highly specialized release sites in the active zone (AZ). However, the spatiotemporal organization of release at active synapses remains elusive, in part owing to the extremely small size of the AZ and the limited resolution of conventional approaches. Recent advances in fluorescence nanoscopy have revolutionized direct investigation of presynaptic release organization and dynamics. We discuss here recent nanoscopy-based studies of the molecular architecture, the spatial organization and dynamic regulation of release sites, and the mechanisms of release site replenishment. These findings have uncovered previously unknown levels of structural and functional organization at central synapses, with important implications for synaptic transmission and plasticity.
Topics: Animals; Exocytosis; Humans; Nanotechnology; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 31176424
DOI: 10.1016/j.tins.2019.03.001 -
Neuron Dec 2001In this issue of Neuron, DeVries (2001) describes experiments suggesting that acidification of the synaptic cleft can reduce Ca2+ channel activity and thereby act as a... (Review)
Review
In this issue of Neuron, DeVries (2001) describes experiments suggesting that acidification of the synaptic cleft can reduce Ca2+ channel activity and thereby act as a brake on tonic synaptic release of glutamate from cone cells. This work hints at a potentially important new facet to the regulation of synaptic transmission.
Topics: Animals; Presynaptic Terminals; Protons; Synaptic Transmission
PubMed: 11754826
DOI: 10.1016/s0896-6273(01)00549-9 -
Molecular Interventions Oct 2010How are synapses made? This question is one of the most important issues in neurobiology today and has been the subject of intense study in recent years. This review... (Review)
Review
How are synapses made? This question is one of the most important issues in neurobiology today and has been the subject of intense study in recent years. This review focuses on the mechanisms of presynaptic terminal formation in the mammalian central nervous system. Building a synapse requires stabilization of contacts between axons and dendrites and formation of synaptic subcellular structures. Here, we discuss what determines where and when synapses form, how components of the nascent presynaptic terminal accumulate at the site of synapse formation, and whether assembly occurs via an ordered process dependent on a master organizer. Understanding synapse formation in the central nervous system is relevant for understanding and treating brain diseases as diverse as autism, epilepsy, anxiety disorders, brain injury, and Alzheimer's disease.
Topics: Animals; Axons; Dendrites; Humans; Mammals; Nerve Tissue Proteins; Presynaptic Terminals; Synapses
PubMed: 21045242
DOI: 10.1124/mi.10.5.5 -
FEBS Letters Nov 2008The presynaptic P2X7 receptor (P2X7R) plays an important role in the modulation of transmitter release. We recently demonstrated that, in nerve terminals of the adult...
The presynaptic P2X7 receptor (P2X7R) plays an important role in the modulation of transmitter release. We recently demonstrated that, in nerve terminals of the adult rat cerebral cortex, P2X7R activation induced Ca2+-dependent vesicular glutamate release and significant Ca2+-independent glutamate efflux through the P2X7R itself. In the present study, we investigated the effect of the new selective P2X(7)R competitive antagonist 3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methyl pyridine (A-438079) on cerebrocortical terminal intracellular calcium (intrasynaptosomal calcium concentration;[Ca2+](i) signals and glutamate release, and evaluated whether P2X7R immunoreactivity was consistent with these functional tests. A-438079 inhibited functional responses. P2X7R immunoreactivity was found in about 45% of cerebrocortical terminals, including glutamatergic and non-glutamatergic terminals. This percentage was similar to that of synaptosomes showing P2X7R-mediated [Ca2+]i signals. These findings provide compelling evidence of functional presynaptic P2X7R in cortical nerve terminals.
Topics: Animals; Cerebral Cortex; Male; Presynaptic Terminals; Purinergic P2 Receptor Antagonists; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2; Receptors, Purinergic P2X7; Synaptosomes; Tetrazoles
PubMed: 18977353
DOI: 10.1016/j.febslet.2008.10.041 -
BioMed Research International 2017Presynaptic and postsynaptic neurotoxins are proteins which act at the presynaptic and postsynaptic membrane. Correctly predicting presynaptic and postsynaptic...
Presynaptic and postsynaptic neurotoxins are proteins which act at the presynaptic and postsynaptic membrane. Correctly predicting presynaptic and postsynaptic neurotoxins will provide important clues for drug-target discovery and drug design. In this study, we developed a theoretical method to discriminate presynaptic neurotoxins from postsynaptic neurotoxins. A strict and objective benchmark dataset was constructed to train and test our proposed model. The dipeptide composition was used to formulate neurotoxin samples. The analysis of variance (ANOVA) was proposed to find out the optimal feature set which can produce the maximum accuracy. In the jackknife cross-validation test, the overall accuracy of 94.9% was achieved. We believe that the proposed model will provide important information to study neurotoxins.
Topics: Amino Acids; Computational Biology; Humans; Models, Theoretical; Neurotoxins; Presynaptic Terminals
PubMed: 28303250
DOI: 10.1155/2017/3267325 -
Nature Communications Oct 2015It remains unclear how readiness for Ca(2+)-dependent exocytosis depends on varying degrees of SNARE complex assembly. Here we directly investigate the SNARE assembly...
It remains unclear how readiness for Ca(2+)-dependent exocytosis depends on varying degrees of SNARE complex assembly. Here we directly investigate the SNARE assembly using two-photon fluorescence lifetime imaging (FLIM) of Förster resonance energy transfer (FRET) between three pairs of neuronal SNAREs in presynaptic boutons and pancreatic β cells in the islets of Langerhans. These FRET probes functionally rescue their endogenous counterparts, supporting ultrafast exocytosis. We show that trans-SNARE complexes accumulated in the active zone, and estimate the number of complexes associated with each docked vesicle. In contrast, SNAREs were unassembled in resting state, and assembled only shortly prior to insulin exocytosis, which proceeds slowly. We thus demonstrate that distinct states of fusion readiness are associated with SNARE complex formation. Our FRET/FLIM approaches enable optical imaging of fusion readiness in both live and chemically fixed tissues.
Topics: Animals; Exocytosis; Fluorescence Resonance Energy Transfer; Insulin-Secreting Cells; Mice; Mice, Inbred C57BL; Optical Imaging; Presynaptic Terminals; SNARE Proteins
PubMed: 26439845
DOI: 10.1038/ncomms9531 -
Acta Neuropathologica 1996Following selective neuronal death, numerous presynaptic terminals maintain their structural integrity in the brain region. The role that these remaining presynaptic...
Following selective neuronal death, numerous presynaptic terminals maintain their structural integrity in the brain region. The role that these remaining presynaptic terminals play in the brain region showing selective neuronal death is not known. In the present study, we investigated the possibility that brief transient ischemia induces an excessive release of glutamate from the remaining presynaptic terminals, which then spreads by diffusion. The glutamate could act as an excitotoxin and be a pathogenic factor in the local injured brain region. Transient ischemia of 3.5 min duration was used in the gerbil as a pretreatment to obtain hippocampal CA1 in which most of postsynaptic neurons were eliminated but numerous presynaptic terminals remained normal. At 10-14 days after the pretreatment, brain microdialysis experiments were performed in vivo in the CA1 to measure the levels of extracellular glutamate induced by 5 min ischemia. Prior to 5 min ischemia the basal concentration of glutamate in the CA1 was the same as that observed in gerbils that had been subjected to sham pretreatment. During 5 min ischemia, no significant increase in glutamate was induced in the CA1 which showed selective neuronal death. However, a massive increase in glutamate was induced in the CA1 of the sham-pretreated gerbils. These results suggest that the remaining presynaptic terminals are unlikely to play a pathogenic role in the CA1 after selective neuronal death has occurred.
Topics: Animals; Brain Ischemia; Cell Death; Gerbillinae; Glutamic Acid; Hippocampus; Male; Microdialysis; Neurons; Presynaptic Terminals
PubMed: 8773144
DOI: 10.1007/s004010050390 -
The Journal of Comparative Neurology Aug 2021The basolateral amygdala (BLA), a region critical for emotional processing, is the limbic hub that is connected with various brain regions. BLA neurons are classified...
The basolateral amygdala (BLA), a region critical for emotional processing, is the limbic hub that is connected with various brain regions. BLA neurons are classified into different subtypes that exhibit differential projection patterns and mediate distinct emotional behaviors; however, little is known about their presynaptic input patterns. In this study, we employed projection-specific monosynaptic rabies virus tracing to identify the direct monosynaptic inputs to BLA subtypes. We found that each neuronal subtype receives long-range projection input from specific brain regions. In contrast to their specific axonal projection patterns, all BLA neuronal subtypes exhibited relatively similar input patterns. This anatomical organization supports the idea that the BLA is a central integrator that associates sensory information in different modalities with valence and sends associative information to behaviorally relevant brain regions.
Topics: Animals; Basolateral Nuclear Complex; Brain Mapping; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Neurons; Presynaptic Terminals
PubMed: 33797073
DOI: 10.1002/cne.25149 -
The Journal of Neuroscience : the... Sep 2020Multiple forms of homeostasis influence synaptic function under diverse activity conditions. Both presynaptic and postsynaptic forms of homeostasis are important, but...
Multiple forms of homeostasis influence synaptic function under diverse activity conditions. Both presynaptic and postsynaptic forms of homeostasis are important, but their relative impact on fidelity is unknown. To address this issue, we studied auditory nerve synapses onto bushy cells in the cochlear nucleus of mice of both sexes. These synapses undergo bidirectional presynaptic and postsynaptic homeostatic changes with increased and decreased acoustic stimulation. We found that both young and mature synapses exhibit similar activity-dependent changes in short-term depression. Experiments using chelators and imaging both indicated that presynaptic Ca influx decreased after noise exposure, and increased after ligating the ear canal. By contrast, Ca cooperativity was unaffected. Experiments using specific antagonists suggest that occlusion leads to changes in the Ca channel subtypes driving neurotransmitter release. Furthermore, dynamic-clamp experiments revealed that spike fidelity primarily depended on changes in presynaptic depression, with some contribution from changes in postsynaptic intrinsic properties. These experiments indicate that presynaptic Ca influx is homeostatically regulated to enhance synaptic fidelity. Homeostatic mechanisms in synapses maintain stable function in the face of different levels of activity. Both juvenile and mature auditory nerve synapses onto bushy cells modify short-term depression in different acoustic environments, which raises the question of what the underlying presynaptic mechanisms are and the relative importance of presynaptic and postsynaptic contributions to the faithful transfer of information. Changes in short-term depression under different acoustic conditions were a result of changes in presynaptic Ca influx. Spike fidelity was affected by both presynaptic and postsynaptic changes after ear occlusion and was only affected by presynaptic changes after noise-rearing. These findings are important for understanding regulation of auditory synapses under normal conditions and also in disorders following noise exposure or conductive hearing loss.
Topics: Animals; Auditory Perception; Calcium; Cochlear Nerve; Cochlear Nucleus; Female; Homeostasis; Male; Mice; Mice, Inbred CBA; Neuronal Plasticity; Noise; Presynaptic Terminals; Synaptic Potentials
PubMed: 32747441
DOI: 10.1523/JNEUROSCI.1175-19.2020 -
Journal of Neurophysiology May 2019Many synapses, including parallel fiber synapses in the cerebellum, express presynaptic GABA receptors. However, reports of the functional consequences of presynaptic...
Many synapses, including parallel fiber synapses in the cerebellum, express presynaptic GABA receptors. However, reports of the functional consequences of presynaptic GABA receptor activation are variable across synapses, from inhibition to enhancement of transmitter release. We find that presynaptic GABA receptor function is bidirectional at parallel fiber synapses depending on GABA concentration and modulation of GABA receptors in mice. Activation of GABA receptors by low GABA concentrations enhances glutamate release, whereas activation of receptors by higher GABA concentrations inhibits release. Furthermore, blocking GABA receptors reduces GABA receptor currents and shifts presynaptic responses toward greater enhancement of release across a wide range of GABA concentrations. Conversely, enhancing GABA receptor currents with ethanol or neurosteroids shifts responses toward greater inhibition of release. The ability of presynaptic GABA receptors to enhance or inhibit transmitter release at the same synapse depending on activity level provides a new mechanism for fine control of synaptic transmission by GABA and may explain conflicting reports of presynaptic GABA receptor function across synapses. GABA receptors are widely expressed at presynaptic terminals in the central nervous system. However, previous reports have produced conflicting results on the function of these receptors at different synapses. We show that presynaptic GABA receptor function is strongly dependent on the level of receptor activation. Low levels of receptor activation enhance transmitter release, whereas higher levels of activation inhibit release at the same synapses. This provides a novel mechanism by which presynaptic GABA receptors fine-tune synaptic transmission.
Topics: Animals; Brain; Exocytosis; Female; Glutamic Acid; Male; Mice; Mice, Inbred C57BL; Presynaptic Terminals; Receptors, GABA-A; Synaptic Potentials
PubMed: 30892973
DOI: 10.1152/jn.00779.2018