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The Journal of Physiology Jul 2015Here we demonstrate presynaptic responses and mechanisms of increased vesicular glutamate release during in vitro ischaemia in the calyx of Held terminal, an...
KEY POINTS
Here we demonstrate presynaptic responses and mechanisms of increased vesicular glutamate release during in vitro ischaemia in the calyx of Held terminal, an experimentally accessible presynaptic terminal in the CNS. The ischaemia-induced increase in presynaptic Ca(2+) was mediated by both Ca(2+) influx and Ca(2+) -induced Ca(2+) release from intracellular stores. The reverse operation of the plasma membrane Na(+) /Ca(2+) exchanger (NCX) plays a key role in Ca(2+) influx for triggering Ca(2+) release from intracellular stores at presynaptic terminals during in vitro ischaemia. Ca(2+) uptake via NCX underlies the ischaemia-induced Ca(2+) rise and the consequent increase in vesicular glutamate release from presynaptic terminals in the early phase of brain ischaemia.
ABSTRACT
An early consequence of brain ischaemia is an increase in vesicular glutamate release from presynaptic terminals. However, the mechanisms of this increased glutamate release are not fully understood. Here we studied presynaptic responses and mechanisms of increased glutamate release during in vitro ischaemia, using pre- and postsynaptic whole-cell recordings and presynaptic Ca(2+) imaging at the calyx of Held synapse in rat brainstem slices. Consistent with results from other brain regions, in vitro ischaemia significantly increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) without affecting their amplitude, suggesting that ischaemia enhances vesicular glutamate release from presynaptic terminals. We found that ischaemia-induced vesicular glutamate release was dependent on a rise in basal Ca(2+) at presynaptic terminals, which resulted from extracellular Ca(2+) influx and Ca(2+) release from intracellular stores. During early ischaemia, increased Ca(2+) influx into presynaptic terminals was due to reverse operation of the plasma membrane Na(+) /Ca(2+) exchanger (NCX) rather than presynaptic depolarization or voltage-activated Ca(2+) currents. KB-R7943, an inhibitor of NCX, prevented the ischaemia-induced increases in presynaptic Ca(2+) and vesicular glutamate release. In addition, the removal of extracellular Na(+) completely inhibited the ischaemia-induced Ca(2+) rise. It therefore appears that a link between Na(+) accumulation and Ca(2+) uptake via NCX underlies the ischaemia-induced Ca(2+) rise and the consequent increase in vesicular glutamate release from presynaptic terminals in the early phase of brain ischaemia.
Topics: Animals; Brain Stem; Calcium Signaling; Cell Hypoxia; Exocytosis; Glutamic Acid; Oxygen; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Sodium-Calcium Exchanger; Synaptic Potentials; Synaptic Vesicles
PubMed: 25833340
DOI: 10.1113/JP270060 -
The Journal of Physiology Dec 2003Exocytosis of neurotransmitter from a synaptic vesicle is followed by efficient retrieval of its constituent membrane and proteins. Real-time measurements indicate that... (Review)
Review
Exocytosis of neurotransmitter from a synaptic vesicle is followed by efficient retrieval of its constituent membrane and proteins. Real-time measurements indicate that fast and slow modes of retrieval operate in parallel at a number of presynaptic terminals. Two mechanisms can be distinguished by electron microscopy: clathrin-mediated retrieval of small vesicles and bulk retrieval of large cisternae. Methods that investigate the behaviour of individual vesicles have recently demonstrated a third route of retrieval: the rapid reversal of a pore-like connection between the vesicle and surface ('kiss-and-run'). Key aims for the future are to identify the molecules underlying different mechanisms of endocytosis at the synapse and the signals that select between them.
Topics: Animals; Clathrin; Dynamins; Endocytosis; Hippocampus; Kinetics; Microscopy, Electron; Models, Neurological; Neuromuscular Junction; Presynaptic Terminals; Synapses
PubMed: 12963793
DOI: 10.1113/jphysiol.2003.049221 -
Experimental Cell Research Jul 2015The function of endosomes and of endosome-like structures in the presynaptic compartment is still controversial. This is in part due to the absence of a consensus on... (Review)
Review
The function of endosomes and of endosome-like structures in the presynaptic compartment is still controversial. This is in part due to the absence of a consensus on definitions and markers for these compartments. Synaptic endosomes are sometimes seen as stable organelles, permanently present in the synapse. Alternatively, they are seen as short-lived intermediates in synaptic vesicle recycling, arising from the endocytosis of large vesicles from the plasma membrane, or from homotypic fusion of small vesicles. In addition, the potential function of the endosome is largely unknown in the synapse. Some groups have proposed that the endosome is involved in the sorting of synaptic vesicle proteins, albeit others have produced data that deny this possibility. In this review, we present the existing evidence for synaptic endosomes, we discuss their potential functions, and we highlight frequent technical pitfalls in the analysis of this elusive compartment. We also sketch a roadmap to definitely determine the role of synaptic endosomes for the synaptic vesicle cycle. Finally, we propose a common definition of synaptic endosome-like structures.
Topics: Animals; Endocytosis; Endosomes; Humans; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 25939282
DOI: 10.1016/j.yexcr.2015.04.017 -
Current Opinion in Neurobiology Aug 2018Research over the past half a century has revealed remarkable diversity among chemical synapses of the CNS. The structural, functional and molecular diversity of... (Review)
Review
Research over the past half a century has revealed remarkable diversity among chemical synapses of the CNS. The structural, functional and molecular diversity of synapses was mainly concluded from studying different synapses in distinct brain regions and preparations. It is not surprising that synapses made by molecularly distinct pre-synaptic and post-synaptic cells display different morphological and functional properties with distinct underlying molecular mechanisms. However, synapses made by a single presynaptic cell onto distinct types of postsynaptic cells, or distinct presynaptic inputs onto a single postsynaptic cell, also show remarkable heterogeneity. Here, by reviewing recent experiments, I suggest that robust functional diversity can be achieved by building synapses from the same molecules, but using different numbers, densities and nanoscale arrangements.
Topics: Animals; Brain; Calcium; Neurotransmitter Agents; Presynaptic Terminals; Synapses; Synaptic Membranes
PubMed: 29353084
DOI: 10.1016/j.conb.2018.01.001 -
Journal of Alzheimer's Disease : JAD 2024A key aspect of synaptic dysfunction in Alzheimer's disease (AD) is loss of synaptic proteins. Previous publications showed that the presynaptic machinery is more... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A key aspect of synaptic dysfunction in Alzheimer's disease (AD) is loss of synaptic proteins. Previous publications showed that the presynaptic machinery is more strongly affected than postsynaptic proteins. However, it has also been reported that presynaptic protein loss is highly variable and shows region- and protein-specificity.
OBJECTIVE
The objective of this meta-analysis was to provide an update on the available literature and to further characterize patterns of presynaptic protein loss in AD.
METHODS
Systematic literature search was conducted for studies published between 2015-2022 which quantified presynaptic proteins in postmortem tissue from AD patients and healthy controls. Three-level random effects meta-analyses of twenty-two identified studies was performed to characterize overall presynaptic protein loss and changes in specific regions, proteins, protein families, and functional categories.
RESULTS
Meta-analysis confirmed overall loss of presynaptic proteins in AD patients. Subgroup analysis revealed region specificity of protein loss, with largest effects in temporal and frontal cortex. Results concerning different groups of proteins were also highly variable. Strongest and most consistently affected was the family of synaptosome associated proteins, especially SNAP25. Among the most severely affected were proteins regulating dense core vesicle exocytosis and the synaptic vesicle cycle.
CONCLUSIONS
Results confirm previous literature related to presynaptic protein loss in AD patients and provide further in-depth characterization of most affected proteins and presynaptic functions.
Topics: Humans; Alzheimer Disease; Proteins; Presynaptic Terminals
PubMed: 38073390
DOI: 10.3233/JAD-231034 -
Seminars in Cell & Developmental Biology Oct 2019In sympathetic neurons innervating the heart, action potentials activate voltage-gated Ca channels and evoke Ca entry into presynaptic terminals triggering... (Review)
Review
In sympathetic neurons innervating the heart, action potentials activate voltage-gated Ca channels and evoke Ca entry into presynaptic terminals triggering neurotransmitter release. Binding of transmitters to specific receptors stimulates signal transduction pathways that cause changes in cardiac function. The mechanisms contributing to presynaptic Ca dynamics involve regulation of endogenous Ca buffers, in particular the endoplasmic reticulum, mitochondria and cyclic nucleotide targeted pathways. The purpose of this review is to summarize and highlight recent findings about Ca homeostasis in cardiac sympathetic neurons and how modulation of second messengers can drive neurotransmission and affect myocyte excitability in cardiovascular disease. Moreover, we discuss the underlying mechanism of abnormal intracellular Ca homeostasis and signaling in these neurons, and speculate on the role of phosphodiesterases as a therapeutic target to restore normal autonomic transmission in disease states of overactivity.
Topics: Animals; Calcium Channels; Cardiovascular Diseases; Humans; Myocytes, Cardiac; Nucleotides, Cyclic; Phosphoric Diester Hydrolases; Presynaptic Terminals
PubMed: 30658154
DOI: 10.1016/j.semcdb.2019.01.010 -
Journal of Neurophysiology Jan 2016Action potential (AP) propagation in presynaptic axons of the crayfish opener neuromuscular junction (NMJ) was investigated by simultaneously recording from a terminal...
Action potential (AP) propagation in presynaptic axons of the crayfish opener neuromuscular junction (NMJ) was investigated by simultaneously recording from a terminal varicosity and a proximal branch. Although orthodromically conducting APs could be recorded in terminals with amplitudes up to 70 mV, depolarizing steps in terminals to -20 mV or higher failed to fire APs. Patch-clamp recordings did detect Na(+) current (INa) in most terminals. The INa exhibited a high threshold and fast activation rate. Local perfusion of Na(+)-free saline showed that terminal INa contributed to AP waveform by slightly accelerating the rising phase and increasing the peak amplitude. These findings suggest that terminal INa functions to "touch up" but not to generate APs.
Topics: Action Potentials; Animals; Astacoidea; Female; Male; Neuromuscular Junction; Presynaptic Terminals; Sodium
PubMed: 26561611
DOI: 10.1152/jn.00959.2015 -
The Journal of Neuroscience : the... Aug 2016
Review
Topics: Animals; Charcot-Marie-Tooth Disease; Humans; Neuromuscular Junction; Presynaptic Terminals; Synaptic Transmission
PubMed: 27488627
DOI: 10.1523/JNEUROSCI.1515-16.2016 -
The Journal of Physiology Feb 2016Synaptic communication between neurons is a highly dynamic process involving specialized structures. At the level of the presynaptic terminal, neurotransmission is... (Review)
Review
Synaptic communication between neurons is a highly dynamic process involving specialized structures. At the level of the presynaptic terminal, neurotransmission is ensured by fusion of vesicles to the membrane, which releases neurotransmitter in the synaptic cleft. Depending on the level of activity experienced by the terminal, the spatiotemporal properties of calcium invasion will dictate the timing and the number of vesicles that need to be released. Diverse presynaptic firing patterns are translated to neurotransmitter release with a distinct temporal feature. Complex patterns of neurotransmitter release can be achieved when different vesicles respond to distinct calcium dynamics in the presynaptic terminal. Specific vesicles from different pools are recruited during various modes of release as the particular molecular composition of their membrane proteins define their functional properties. Such diversity endows the presynaptic terminal with the ability to respond to distinct physiological signals via the mobilization of specific subpopulation of vesicles. There are several mechanisms by which a diverse vesicle population could be generated in single presynaptic terminals, including distinct recycling pathways that utilize various adaptor proteins. Several additional factors could potentially contribute to the development of a heterogeneous vesicle pool such as specialized release sites, spatial segregation within the terminal and specialized delivery pathways. Among these factors molecular heterogeneity plays a central role in defining the functional properties of different subpopulations of vesicles.
Topics: Animals; Calcium; Exocytosis; Humans; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 26614712
DOI: 10.1113/JP270194 -
Synapse (New York, N.Y.) Mar 2003Changes in the amplitudes of signals conveyed at synaptic contacts between neurons underlie many brain functions and pathologies. Here we review the possible... (Review)
Review
Changes in the amplitudes of signals conveyed at synaptic contacts between neurons underlie many brain functions and pathologies. Here we review the possible determinants of the amplitude and plasticity of the elementary postsynaptic signal, the miniature. In the absence of a definite understanding of the molecular mechanism releasing transmitters, we investigated a possible alternative interpretation. Classically, both the quantal theory and the vesicle theory predict that the amount of transmitter producing a miniature is determined presynaptically prior to release and that rapid changes in miniature amplitude reflect essentially postsynaptic alterations. However, recent data indicates that short-term and long-lasting changes in miniature amplitude are in large part due to changes in the amount of transmitter in individual released packets that show no evidence of preformation. Current representations of transmitter release derive from basic properties of neuromuscular transmission and endocrine secretion. Reexamination of overlooked properties of these two systems indicate that the amplitude of miniatures may depend as much, if not more, on the Ca(2+) signals in the presynaptic terminal than on the number of postsynaptic receptors available or on vesicle's contents. Rapid recycling of transmitter and its possible adsorption at plasma and vesicle lumenal membrane surfaces suggest that exocytosis may reflect membrane traffic rather than actual transmitter release. This led us to reconsider the disregarded hypothesis introduced by Fatt and Katz (1952; J Physiol 117:109-128) that the excitability of the release site may account for the "quantal effect" in fast synaptic transmission. In this case, changes in excitability of release sites would contribute to the presynaptic quantal plasticity that is often recorded.
Topics: Animals; Biological Transport; Calcium; Calcium Signaling; Exocytosis; Glycocalyx; Humans; Models, Neurological; Neuronal Plasticity; Neurotransmitter Agents; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 12494401
DOI: 10.1002/syn.10161