scholarly journals The vesicular release probability sets the strength of individual Schaffer collateral synapses

2020 ◽  
Author(s):  
Céline D. Dürst ◽  
J. Simon Wiegert ◽  
Christian Schulze ◽  
Nordine Helassa ◽  
Katalin Török ◽  
...  
Keyword(s):  
Schaffer Collateral ◽  
Release Probability ◽  
Single Axon ◽  
Vesicular Release ◽  
High Calcium ◽  
Fusion Site ◽  
Presynaptic Boutons ◽  
The Brain ◽  
Measured Response ◽  
Single Vesicle

AbstractInformation processing in the brain is controlled by quantal release of neurotransmitters, a tightly regulated process. Even in a single axon, presynaptic boutons differ in the number of docked vesicles, but it is not known if the vesicular release probability (pves) is homogenous or variable between individual boutons. We optically measured evoked transmitter release at individual Schaffer collateral synapses using the genetically encoded glutamate sensor iGluSnFR, localizing the fusion site on the bouton with high spatiotemporal precision. Fitting a binomial model to measured response amplitude distributions allowed us to extract the quantal parameters N, pves, and q. Schaffer collateral boutons typically released only a single vesicle under low pves conditions and switched to multivesicular release in high calcium saline. We found that pves was highly variable between individual boutons and had a dominant impact on presynaptic output.

scholarly journals The vesicular release probability sets the strength of individual Schaffer collateral synapses

2020 ◽  
Author(s):  
Céline Dürst ◽  
J. Simon Wiegert ◽  
Christian Schulze ◽  
Nordine Helassa ◽  
Katalin Torok ◽  
...  
Keyword(s):  
Schaffer Collateral ◽  
Release Probability ◽  
Single Axon ◽  
Vesicular Release ◽  
High Calcium ◽  
Fusion Site ◽  
Presynaptic Boutons ◽  
The Brain ◽  
Measured Response ◽  
Single Vesicle

Abstract Information processing in the brain is controlled by quantal release of neurotransmitters, a tightly regulated process. Even in a single axon, presynaptic boutons differ in the number of docked vesicles, but it is not known if the vesicular release probability (pves) is homogenous or variable between individual boutons. We optically measured evoked transmitter release at individual Schaffer collateral synapses using the genetically encoded glutamate sensor iGluSnFR, localizing the fusion site on the bouton with high spatiotemporal precision. Fitting a binomial model to measured response amplitude distributions allowed us to extract the quantal parameters N, pves, and q. Schaffer collateral boutons typically released only a single vesicle under low pves conditions and switched to multivesicular release in high calcium saline. We found that pves was highly variable between individual boutons and had a dominant impact on presynaptic output.

scholarly journals Vesicular Antipsychotic Drug Release Evokes an Extra Phase of Dopamine Transmission

2019 ◽  
Vol 46 (3) ◽  
pp. 643-649 ◽  
Author(s):  
Seth H Walters ◽  
Edwin S Levitan
Keyword(s):  
Drug Release ◽  
Antipsychotic Drug ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Dopamine Release ◽  
Fast Scan Cyclic Voltammetry ◽  
Weak Bases ◽  
Vesicular Release ◽  
Stimulation Experiments ◽  
The Brain

Abstract Many psychiatric drugs are weak bases that accumulate in and are released from synaptic vesicles, but the functional impact of vesicular drug release is largely unknown. Here, we examine the effect of vesicular release of the anxiolytic antipsychotic drug cyamemazine on electrically evoked striatal dopamine responses with fast scan cyclic voltammetry. Remarkably, in the presence of nanomolar extracellular cyamemazine, vesicular cyamemazine release in the brain slice can increase dopamine responses 30-fold. Kinetic analysis and multiple stimulation experiments show that this occurs by inducing delayed emptying of the releasable dopamine pool. Also consistent with increased dopamine release, an antagonist (dihydro-β-erythroidine) implicates nicotinic acetylcholine receptors, which can directly cause dopamine release, in the vesicular cyamemazine effect. Therefore, vesicular release of cyamemazine can dramatically enhance dopaminergic synaptic transmission, possibly by recruiting an excitatory cholinergic input to induce an extra phase of release. More generally, this study suggests that synaptic drug release following vesicular accumulation by acidic trapping can expand psychiatric drug pharmacodynamics.

scholarly journals Examining molecular determinants underlying heterogeneity of synaptic release probability using optical quantal imaging

2017 ◽  
Author(s):  
Yulia Akbergenova ◽  
Yao V. Zhang ◽  
Shirley Weiss-Sharabi ◽  
Karen L. Cunningham ◽  
J. Troy Littleton
Keyword(s):  
Glutamate Receptor ◽  
Neuromuscular Junctions ◽  
Receptor Activation ◽  
Distinct Pattern ◽  
Strongly Correlated ◽  
Release Probability ◽  
Molecular Determinants ◽  
Synaptotagmin 1 ◽  
Developmental Analysis ◽  
Single Vesicle

AbstractNeurons communicate through neurotransmitter release at specialized synaptic regions known as active zones (AZs). Using transgenic biosensors to image postsynaptic glutamate receptor activation following single vesicle fusion events at Drosophila neuromuscular junctions, we analyzed release probability (Pr) maps for a defined connection with ~300 AZs between synaptic partners. Although Pr was very heterogeneous, it represented a stable and unique feature of each AZ. Pr heterogeneity was not abolished in mutants lacking Synaptotagmin 1, suggesting the AZ itself is likely to harbor a key determinant(s). Indeed, AZ Pr was strongly correlated with presynaptic Ca2+ channel density and Ca2+ influx at single release sites. In addition, Pr variability was reflected in the postsynaptic compartment, as high Pr AZs displayed a distinct pattern of glutamate receptor clustering. Developmental analysis suggests that high Pr sites emerge from earlier formed AZs, with a temporal maturation in transmission strength occurring over several days.

Craniosynostosis

Neurosurgery ◽  
1981 ◽  
Vol 9 (4) ◽  
pp. 366-372 ◽  
Author(s):  
Peter W. Carmel ◽  
Martin G. Luken ◽  
George F. Ascherl
Keyword(s):  
Skull Base ◽  
Brain Structures ◽  
Local Pressure ◽  
Computed Tomographic ◽  
Current Trends ◽  
Fusion Site ◽  
Serial Scanning ◽  
Tissue Abnormalities ◽  
The Brain

Abstract Computed tomography has proven useful in children with craniosynostosis for the evaluation of deformity of the skull base. calvarium. and parenchymal brain structures. A retrospective analysis of 24 children seen during a 4-year period who had adequate preoperative, postoperative. and follow-up scans was carried out. Bone windows were used. and both bone thinning adjacent to fused sutures and thickening of affected sutures were demonstrated. Changes in calvarial contour were easily followed. Current trends in craniofacial reconstructive surgery have placed emphasis on skull base abnormalities: these are readily measured on axial computed tomographic (CT) sections. and postoperative progress may be monitored by serial scanning. In addition, new data revealing distortion of brain structures and cerebrospinal fluid pathways in these children have been obtained with CT scans. These soft tissue abnormalities had not been appreciated before the CT era, and they add a new dimension to the evaluation of these disorders. We think that these abnormalities indicate a local pressure increase on the brain at the fusion site. The restoration of parenchymal changes toward normal during the postoperative period correlated well with cosmetic improvement.

scholarly journals Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a+/− mouse model of Dravet syndrome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kouya Uchino ◽  
Hiroyuki Kawano ◽  
Yasuyoshi Tanaka ◽  
Yuna Adaniya ◽  
Ai Asahara ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dravet Syndrome ◽  
Inhibitory Synapses ◽  
Wild Type ◽  
Inhibitory Synaptic Transmission ◽  
Postsynaptic Currents ◽  
Vesicular Release ◽  
A Subunit ◽  
Proportional Increase ◽  
The Brain

AbstractDravet syndrome (DS) is an intractable form of childhood epilepsy that occurs in infancy. More than 80% of all patients have a heterozygous abnormality in the SCN1A gene, which encodes a subunit of Na+ channels in the brain. However, the detailed pathogenesis of DS remains unclear. This study investigated the synaptic pathogenesis of this disease in terms of excitatory/inhibitory balance using a mouse model of DS. We show that excitatory postsynaptic currents were similar between Scn1a knock-in neurons (Scn1a+/− neurons) and wild-type neurons, but inhibitory postsynaptic currents were significantly lower in Scn1a+/− neurons. Moreover, both the vesicular release probability and the number of inhibitory synapses were significantly lower in Scn1a+/− neurons compared with wild-type neurons. There was no proportional increase in inhibitory postsynaptic current amplitude in response to increased extracellular Ca2+ concentrations. Our study revealed that the number of inhibitory synapses is significantly reduced in Scn1a+/− neurons, while the sensitivity of inhibitory synapses to extracellular Ca2+ concentrations is markedly increased. These data suggest that Ca2+ tethering in inhibitory nerve terminals may be disturbed following the synaptic burst, likely leading to epileptic symptoms.

scholarly journals Area-specific synapse structure in branched axons reveals a subcellular level of complexity in thalamocortical networks

2019 ◽  
Author(s):  
Javier Rodriguez-Moreno ◽  
Cesar Porrero ◽  
Astrid Rollenhagen ◽  
Mario Rubio-Teves ◽  
Diana Casas-Torremocha ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Thalamic Nucleus ◽  
Circuit Complexity ◽  
Zone Size ◽  
Single Axon ◽  
3D Electron Microscopy ◽  
Structural Differences ◽  
Vesicle Pool ◽  
The Brain ◽  
Subcellular Level

AbstractThalamocortical Posterior nucleus (Po) axons innervating the somatosensory (S1) and motor (MC) vibrissal cortices are key links in the brain neuronal network that allows rodents to explore the environment whisking with their motile vibrissae. Here, using high-end 3D electron microscopy, we demonstrate massive differences between MC vs. S1 Po synapses in a) bouton and active zone size; b) neurotransmitter vesicle pool size; c) mitochondria distribution near synapses; and d) proportion of non-spinous dendrite contacts. These differences are as large, or bigger, than those between Po and ventroposterior thalamic nucleus synapses in S1. Moreover, using single-axon transfection labeling, we show that the structure of boutons in the MC vs. S1 branches of individual Po axons is different. These structural differences parallel striking, recently-discovered divergences in functional efficacy and plasticity between S1 and MC Po synapses, and overall reveal a new, subcellular level of thalamocortical circuit complexity, unaccounted for in current models.

scholarly journals Molecular Determinants of Complexin Clamping in Reconstituted Single-Vesicle Fusion

2021 ◽  
Author(s):  
Manindra Bera ◽  
Sathish Ramakrishnan ◽  
Jeff Coleman ◽  
Shyam S Krishnakumar ◽  
James E Rothman
Keyword(s):  
Specific Interaction ◽  
Vesicle Fusion ◽  
Assembly Process ◽  
Inhibitory Function ◽  
Physiological Relevance ◽  
Vesicular Release ◽  
Molecular Determinants ◽  
Synaptotagmin 1 ◽  
Single Vesicle

Previously we reported that Synaptotagmin-1 and Complexin synergistically clamp the SNARE assembly process to generate and maintain a pool of docked vesicles that fuse rapidly and synchronously upon Ca2+ influx (Ramakrishnan et al. 2020). Here using the same in vitro single-vesicle fusion assay, we establish the molecular details of the Complexin clamp and its physiological relevance. We find that a delay in fusion kinetics, likely imparted by Synaptotagmin-1, is needed for Complexin to block fusion. Systematic truncation/mutational analyses reveal that continuous alpha-helical accessory-central domains of Complexin are essential for its inhibitory function and specific interaction of the accessory helix with the SNAREpins, analogous to the trans clamping model, enhances this functionality. The c-terminal domain promotes clamping by locally elevating Complexin concentration through interactions with the membrane. Further, we find that Complexin likely contributes to rapid Ca2+-synchronized vesicular release by preventing un-initiated fusion rather than by directly facilitating vesicle fusion.

scholarly journals A GRAB sensor reveals activity-dependent non-vesicular somatodendritic adenosine release

2020 ◽  
Author(s):  
Zhaofa Wu ◽  
Yuting Cui ◽  
Huan Wang ◽  
Kun Song ◽  
Zhengwei Yuan ◽  
...  
Keyword(s):  
Calcium Influx ◽  
Purinergic Signaling ◽  
Equilibrative Nucleoside Transporters ◽  
Brain Functions ◽  
Vesicular Release ◽  
Induced Changes ◽  
Retrograde Signal ◽  
Modulating Functions ◽  
Activity Dependent ◽  
The Brain

AbstractThe purinergic signaling molecule adenosine (Ado) modulates many physiological and pathological brain functions,but its spatiotemporal release dynamics in the brain remains largely unknown. We developed a genetically encoded GPCR-Activation–Based Ado sensor (GRABAdo) in which Ado-induced changes in the human A2A receptor are reflected by fluorescence increases. This GRABAdo revealed that neuronal activity-induced extracellular Ado elevation was due to direct Ado release from somatodendritic regions of the neuron, requiring calcium influx through L-type calcium channels, rather than the degradation of extracellular ATP. The Ado release was slow (∼30 s) and depended on equilibrative nucleoside transporters (ENTs) rather than conventional vesicular release mechanisms. Thus, GRABAdo reveals an activity-dependent slow Ado release from somatodendritic region of the neuron, potentially serving modulating functions as a retrograde signal.

scholarly journals Rapid regulation of vesicle priming explains synaptic facilitation despite heterogeneous vesicle:Ca2+ channel distances

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Janus RL Kobbersmed ◽  
Andreas T Grasskamp ◽  
Meida Jusyte ◽  
Mathias A Böhme ◽  
Susanne Ditlevsen ◽  
...  
Keyword(s):  
Super Resolution ◽  
Release Site ◽  
Stochastic Simulations ◽  
Short Term ◽  
Short Term Plasticity ◽  
Release Probability ◽  
Vesicular Release ◽  
Dependent Inhibition ◽  
Super Resolution Microscopy ◽  
Activity Dependent

Chemical synaptic transmission relies on the Ca2+-induced fusion of transmitter-laden vesicles whose coupling distance to Ca2+ channels determines synaptic release probability and short-term plasticity, the facilitation or depression of repetitive responses. Here, using electron- and super-resolution microscopy at the Drosophila neuromuscular junction we quantitatively map vesicle:Ca2+ channel coupling distances. These are very heterogeneous, resulting in a broad spectrum of vesicular release probabilities within synapses. Stochastic simulations of transmitter release from vesicles placed according to this distribution revealed strong constraints on short-term plasticity; particularly facilitation was difficult to achieve. We show that postulated facilitation mechanisms operating via activity-dependent changes of vesicular release probability (e.g. by a facilitation fusion sensor) generate too little facilitation and too much variance. In contrast, Ca2+-dependent mechanisms rapidly increasing the number of releasable vesicles reliably reproduce short-term plasticity and variance of synaptic responses. We propose activity-dependent inhibition of vesicle un-priming or release site activation as novel facilitation mechanisms.

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