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International Journal of Molecular... Dec 2020An action potential (AP) triggers neurotransmitter release from synaptic vesicles (SVs) docking to a specialized release site of presynaptic plasma membrane, the active... (Review)
Review
An action potential (AP) triggers neurotransmitter release from synaptic vesicles (SVs) docking to a specialized release site of presynaptic plasma membrane, the active zone (AZ). The AP simultaneously controls the release site replenishment with SV for sustainable synaptic transmission in response to incoming neuronal signals. Although many studies have suggested that the replenishment time is relatively slow, recent studies exploring high speed resolution have revealed SV dynamics with milliseconds timescale after an AP. Accurate regulation is conferred by proteins sensing Ca entering through voltage-gated Ca channels opened by an AP. This review summarizes how millisecond Ca dynamics activate multiple protein cascades for control of the release site replenishment with release-ready SVs that underlie presynaptic short-term plasticity.
Topics: Animals; Humans; Neuronal Plasticity; Neurotransmitter Agents; Presynaptic Terminals; Synaptic Transmission
PubMed: 33396919
DOI: 10.3390/ijms22010327 -
ELife Apr 2023Control of neurotransmission efficacy is central to theories of how the brain computes and stores information. Presynaptic G-protein coupled receptors (GPCRs) are...
Control of neurotransmission efficacy is central to theories of how the brain computes and stores information. Presynaptic G-protein coupled receptors (GPCRs) are critical in this problem as they locally influence synaptic strength and can operate on a wide range of time scales. Among the mechanisms by which GPCRs impact neurotransmission is by inhibiting voltage-gated calcium (Ca) influx in the active zone. Here, using quantitative analysis of both single bouton Ca influx and exocytosis, we uncovered an unexpected non-linear relationship between the magnitude of action potential driven Ca influx and the concentration of external Ca ([Ca]). We find that this unexpected relationship is leveraged by GPCR signaling when operating at the nominal physiological set point for [Ca], 1.2 mM, to achieve complete silencing of nerve terminals. These data imply that the information throughput in neural circuits can be readily modulated in an all-or-none fashion at the single synapse level when operating at the physiological set point.
Topics: Synapses; Presynaptic Terminals; Synaptic Transmission; Action Potentials; gamma-Aminobutyric Acid; Calcium
PubMed: 37014052
DOI: 10.7554/eLife.83530 -
Cell and Tissue Research Sep 2018The mammalian forebrain is constructed from ensembles of neurons that form local microcircuits giving rise to the exquisite cognitive tasks the mammalian brain can... (Review)
Review
The mammalian forebrain is constructed from ensembles of neurons that form local microcircuits giving rise to the exquisite cognitive tasks the mammalian brain can perform. Hippocampal neuronal circuits comprise populations of relatively homogenous excitatory neurons, principal cells and exceedingly heterogeneous inhibitory neurons, the interneurons. Interneurons release GABA from their axon terminals and are capable of controlling excitability in every cellular compartment of principal cells and interneurons alike; thus, they provide a brake on excess activity, control the timing of neuronal discharge and provide modulation of synaptic transmission. The dendritic and axonal morphology of interneurons, as well as their afferent and efferent connections within hippocampal circuits, is central to their ability to differentially control excitability, in a cell-type- and compartment-specific manner. This review aims to provide an up-to-date compendium of described hippocampal interneuron subtypes, with respect to their morphology, connectivity, neurochemistry and physiology, a full understanding of which will in time help to explain the rich diversity of neuronal function.
Topics: Animals; Cortical Excitability; Dendrites; Glutamic Acid; Hippocampus; Interneurons; Mice; Models, Neurological; Presynaptic Terminals; Rats; Synapses; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 30084021
DOI: 10.1007/s00441-018-2882-2 -
Current Opinion in Neurobiology Aug 2019Ion channels are microscopic pore proteins in the membrane that open and close in response to chemical and electrical stimuli. This simple concept underlies rapid... (Review)
Review
Ion channels are microscopic pore proteins in the membrane that open and close in response to chemical and electrical stimuli. This simple concept underlies rapid electrical signaling in the brain as well as several important aspects of neural plasticity. Although the soma accounts for less than 1% of many neurons by membrane area, it has been the major site of measuring ion channel function. However, the axon is one of the longest processes found in cellular biology and hosts a multitude of critical signaling functions in the brain. Not only does the axon initiate and rapidly propagate action potentials (APs) across the brain but it also forms the presynaptic terminals that convert these electrical inputs into chemical outputs. Here, we review recent advances in the physiological role of ion channels within the diverse landscape of the axon and presynaptic terminals.
Topics: Action Potentials; Axons; Ion Channels; Neurons; Presynaptic Terminals
PubMed: 30784979
DOI: 10.1016/j.conb.2019.01.020 -
Journal of Alzheimer's Disease : JAD 2019It is now more than two decades since amyloid-β (Aβ), the proteolytic product of the amyloid-β protein precursor (AβPP), was first demonstrated to be a normal and... (Review)
Review
It is now more than two decades since amyloid-β (Aβ), the proteolytic product of the amyloid-β protein precursor (AβPP), was first demonstrated to be a normal and soluble product of neuronal metabolism. To date, despite a growing body of evidence suggests its regulatory role on synaptic function, the exact cellular and molecular pathways involved in Aβ-driven synaptic effects remain elusive. This review provides an overview of the mounting evidence showing Aβ-mediated effects on presynaptic functions and neurotransmitter release from axon terminals, focusing on its interaction with synaptic vesicle cycle. Indeed, Aβ peptides have been found to interact with key presynaptic scaffold proteins and kinases affecting the consequential steps of the synaptic vesicle dynamics (e.g., synaptic vesicles exocytosis, endocytosis, and trafficking). Defects in the fine-tuning of synaptic vesicle cycle by Aβ and deregulation of key molecules and kinases, which orchestrate synaptic vesicle availability, may alter synaptic homeostasis, possibly contributing to synaptic loss and cognitive decline. Elucidating the presynaptic mechanisms by which Aβ regulate synaptic transmission is fundamental for a deeper comprehension of the biology of presynaptic terminals as well as of Aβ-driven early synaptic defects occurring in prodromal stage of AD. Moreover, a better understating of Aβ involvement in cellular signal pathways may allow to set up more effective therapeutic interventions by detecting relevant molecular mechanisms, whose imbalance might ultimately lead to synaptic impairment in AD.
Topics: Amyloid beta-Peptides; Animals; Endocytosis; Exocytosis; Humans; Presynaptic Terminals; Synapses; Synaptic Vesicles
PubMed: 31561377
DOI: 10.3233/JAD-190771 -
Brain Research Bulletin Jan 2018One of the main functions of astrocytes is to ensure glutamate homeostasis by glutamate uptake and glutamine synthesis. However, during the past ten years it has become... (Review)
Review
One of the main functions of astrocytes is to ensure glutamate homeostasis by glutamate uptake and glutamine synthesis. However, during the past ten years it has become clear that astrocytes may also induce changes in synaptic glutamate release when respective pathways must cope with the consequences of brain damage or other alterations in their functional requirements. The loss of glutamatergic synapses in Parkinson's and Huntington's disease is likely to associate with a continuous redistribution of presynaptic activity within the pool of surviving synapses, and astrocytes may have a role in the maintenance of independent control at individual glutamate release sites. The rodent striatum should be a good model structure to analyse astrocyte-synapse interactions underlying disease-related plasticity, because it does not itself contain any glutamatergic neurons. Here we examine recent results that may shed light on the mechanisms underlying pathway-specific alterations in the corticostriatal or thalamostriatal synaptic transmission with a possible involvement of astrocytic release or uptake of glutamate. The conclusions emphasize the need of exploring the highly compartmentalised and presumably heterogeneous synapse astrocyte-interactions at a single synapse level.
Topics: Animals; Astrocytes; Corpus Striatum; Humans; Neuronal Plasticity; Presynaptic Terminals
PubMed: 28069435
DOI: 10.1016/j.brainresbull.2017.01.001 -
Synapse (New York, N.Y.) May 2015A key goal in neurobiology is to generate a theoretical framework that merges structural, physiological, and molecular explanations of brain function. These categories... (Review)
Review
A key goal in neurobiology is to generate a theoretical framework that merges structural, physiological, and molecular explanations of brain function. These categories of explanation do not advance in synchrony; advances in one category define new experiments in other categories. For example, the synapse was defined physiologically and biochemically before it was visualized using electron microscopy. Indeed, the original descriptions of synapses in the 1950s were lent credence by the presence of spherical vesicles in presynaptic terminals that were considered to be the substrate for quantal neurotransmission. In the last few decades, our understanding of synaptic function has again been driven by physiological and molecular techniques. The key molecular players for synaptic vesicle structure, mobility and fusion were identified and applications of the patch clamp technique permitted physiological estimation of neurotransmitter release and receptor properties. These advances demand higher resolution structural images of synapses. During the 1990s a second renaissance in cell biology driven by EM was fueled by improved techniques for electron tomography (ET) with the ability to compute virtual images with nm resolution between image planes. Over the last 15 years, ET has been applied to the presynaptic terminal with special attention to the active zone and organelles of the nerve terminal. In this review, we first summarize the technical improvements that have led to a resurgence in utilization of ET and then we summarize new insights gained by the application of ET to reveal the high-resolution structure of the nerve terminal.
Topics: Animals; Electron Microscope Tomography; Humans; Presynaptic Terminals; Synaptic Vesicles
PubMed: 25683026
DOI: 10.1002/syn.21813 -
The Neuroscientist : a Review Journal... Oct 2019Nervous system communication relies on neurotransmitter release for synaptic transmission between neurons. Neurotransmitter is contained within vesicles in presynaptic... (Review)
Review
Nervous system communication relies on neurotransmitter release for synaptic transmission between neurons. Neurotransmitter is contained within vesicles in presynaptic terminals and intraterminal calcium governs the fundamental step of their release into the synaptic cleft. Despite a common dependence on calcium, synaptic transmission and its modulation varies highly across the nervous system. The precise mechanisms that underlie this heterogeneity, however, remain unclear. The present review highlights recent data that reveal vesicles sourced from separate pools define discrete modes of release. A rich diversity of regulatory machinery may further distinguish the different forms of vesicle release, including presynaptic proteins involved in trafficking, alignment, and exocytosis. These multiple vesicle release mechanisms and vesicle pools likely depend on the arrangement of vesicles in relation to specific calcium entry pathways that create compartmentalized spheres of calcium influence (i.e., domains). This diversity permits release specialization. This review details examples of how individual neurons rely on multiple calcium sources and unique regulatory schemes to provide differential release and discrete modulation of neurotransmitter release from specific vesicle pools-as part of network signal integration.
Topics: Animals; Calcium Signaling; Exocytosis; Glutamic Acid; Humans; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 31375041
DOI: 10.1177/1073858419863771 -
Neurochemical Research Mar 2019Presynaptic terminals possess interlocking molecular mechanisms that control exocytosis. An example of such complexity is the modulation of release by presynaptic G... (Review)
Review
Presynaptic terminals possess interlocking molecular mechanisms that control exocytosis. An example of such complexity is the modulation of release by presynaptic G Protein Coupled Receptors (GPCRs). GPCR ubiquity at synapses-GPCRs are present at every studied presynaptic terminal-underlies their critical importance in synaptic function. GPCRs mediate presynaptic modulation by mechanisms including via classical Gα effectors, but membrane-delimited actions of Gβγ can also alter probability of release by altering presynaptic ionic conductances. This directly or indirectly modifies action potential-evoked presynaptic Ca entry. In addition, Gβγ can interact directly with SNARE complexes responsible for synaptic vesicle fusion to reduce peak cleft neurotransmitter concentrations during evoked release. The interaction of Gβγ with SNARE is displaced via competitive interaction with C2AB-domain containing calcium sensors such as synaptotagmin I in a Ca-sensitive manner, restoring exocytosis. Synaptic modulation of this form allows selective inhibition of postsynaptic receptor-mediated responses, and this, in combination with Ca sensitivity of Gβγ effects on SNARE complexes allows for specific behavioral outcomes. One such outcome mediated by 5-HT receptors in the spinal cord seen in all vertebrates shows remarkable synergy between presynaptic effects of Gβγ and postsynaptic 5-HT-mediated changes in activation of Ca-dependent K channels. While acting through entirely separate cellular compartments and signal transduction pathways, these effects converge on the same effect on locomotion and other critical functions of the central nervous system.
Topics: Action Potentials; Animals; Calcium; Exocytosis; Humans; Presynaptic Terminals; SNARE Proteins; Synaptic Transmission
PubMed: 29752624
DOI: 10.1007/s11064-018-2531-x -
Frontiers in Neural Circuits 2020Excitatory synapses in the mammalian cortex are highly diverse, both in terms of their structure and function. However, relationships between synaptic features indicate... (Review)
Review
Excitatory synapses in the mammalian cortex are highly diverse, both in terms of their structure and function. However, relationships between synaptic features indicate they are highly coordinated entities. Imaging techniques, that enable physiology at the resolution of individual synapses to be investigated, have allowed the presynaptic activity level of the synapse to be related to postsynaptic function. This approach has revealed that neuronal activity induces the pre- and post-synapse to be functionally correlated and that subsets of synapses are more susceptible to certain forms of synaptic plasticity. As presynaptic function is often examined in isolation from postsynaptic properties, the effect it has on the post-synapse is not fully understood. However, since postsynaptic receptors at excitatory synapses respond to release of glutamate, it follows that they may be differentially regulated depending on the frequency of its release. Therefore, examining postsynaptic properties in the context of presynaptic function may be a useful way to approach a broad range of questions on synaptic physiology. In this review, we focus on how optophysiology tools have been utilized to study relationships between the pre- and the post-synapse. Multiple imaging techniques have revealed correlations in synaptic properties from the submicron to the dendritic level. Optical tools together with advanced imaging techniques are ideally suited to illuminate this area further, due to the spatial resolution and control they allow.
Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Humans; Neuronal Plasticity; Presynaptic Terminals; Receptors, AMPA; Synapses; Synaptic Potentials; Synaptic Transmission
PubMed: 32308573
DOI: 10.3389/fncir.2020.00009