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Current Opinion in Neurobiology Oct 2022Sustained neurotransmission is driven by a continuous supply of synaptic vesicles to the release sites and modulated by synaptic vesicle dynamics. However, synaptic... (Review)
Review
Sustained neurotransmission is driven by a continuous supply of synaptic vesicles to the release sites and modulated by synaptic vesicle dynamics. However, synaptic vesicle dynamics in synapses remain elusive because of technical limitations. Recent advances in fluorescence imaging techniques have enabled the tracking of single synaptic vesicles in small central synapses in living neurons. Single vesicle tracking has uncovered a wealth of new information about synaptic vesicle dynamics both within and outside presynaptic terminals, showing that single vesicle tracking is an effective tool for studying synaptic vesicle dynamics. Particularly, single vesicle tracking with high spatiotemporal resolution has revealed the dependence of synaptic vesicle dynamics on the location, stages of recycling, and neuronal activity. This review summarizes the recent findings from single synaptic vesicle tracking in small central synapses and their implications in synaptic transmission and pathogenic mechanisms of neurodegenerative diseases.
Topics: Neurons; Presynaptic Terminals; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 35803103
DOI: 10.1016/j.conb.2022.102596 -
Biochimica Et Biophysica Acta.... Nov 2022Adequate homeostasis of lipid, protein and carbohydrate metabolism is essential for cells to perform highly specific tasks in our organism, and the brain, with its... (Review)
Review
Adequate homeostasis of lipid, protein and carbohydrate metabolism is essential for cells to perform highly specific tasks in our organism, and the brain, with its uniquely high energetic requirements, posesses singular characteristics. Some of these are related to its extraordinary dotation of synapses, the specialized subcelluar structures where signal transmission between neurons occurs in the central nervous system. The post-synaptic compartment of excitatory synapses, the dendritic spine, harbors key molecules involved in neurotransmission tightly packed within a minute volume of a few femtoliters. The spine is further compartmentalized into nanodomains that facilitate the execution of temporo-spatially separate functions in the synapse. Lipids play important roles in this structural and functional compartmentalization and in mechanisms that impact on synaptic transmission. This review analyzes the structural and dynamic processes involving lipids at the synapse, highlighting the importance of their homeostatic balance for the physiology of this complex and highly specialized structure, and underscoring the pathologies associated with disbalances of lipid metabolism, particularly in the perinatal and late adulthood periods of life. Although small variations of the lipid profile in the brain take place throughout the adult lifespan, the pathophysiological consequences are clinically manifested mostly during late adulthood. Disturbances in lipid homeostasis in the perinatal period leads to alterations during nervous system development, while in late adulthood they favor the occurrence of neurodegenerative diseases.
Topics: Lipidomics; Lipids; Neurons; Synapses; Synaptic Transmission
PubMed: 35964712
DOI: 10.1016/j.bbamem.2022.184033 -
Developmental Neurobiology May 2017Electrical synapses are finding increasing representation and importance in our understanding of signaling in the nervous system. In contrast to chemical synapses, at... (Review)
Review
Electrical synapses are finding increasing representation and importance in our understanding of signaling in the nervous system. In contrast to chemical synapses, at which molecules are evolutionary conserved, vertebrate and invertebrate electrical synapses represent molecularly different structures that share a common communicating strategy that allows them to serve very similar functions. A better understanding of differences and commonalities regarding the structure, function and regulation of vertebrate and invertebrate electrical synapses will lead to a better understanding of the properties and functional diversity of this modality of synaptic communication. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 517-521, 2017.
Topics: Animals; Electrical Synapses; Synaptic Transmission
PubMed: 28188695
DOI: 10.1002/dneu.22488 -
Vitamins and Hormones 2020The mammalian brain contains many regions which synthesize and release the hormone and transmitter corticotropin releasing factor. This peptide is a key player in the... (Review)
Review
The mammalian brain contains many regions which synthesize and release the hormone and transmitter corticotropin releasing factor. This peptide is a key player in the function of the hypothalamic-pituitary-adrenal axis and has major role in mediating the endocrine limb of the stress response. However, there are several regions outside of the paraventricular nucleus of the hypothalamus which synthesize this peptide in which it has a role more akin to a classical neurotransmitter. A significant body of literature exists in which its role as a transmitter and its cellular effects in many brain regions, as well as how it affects various forms of behavior, is described. However, the receptors which corticotropin releasing factor interacts with in the brain are G-protein coupled receptors, and therefore their activation promotes a multitude of cellular effects. Despite this, comparatively little research has been done to investigate how this peptide affects excitatory synaptic transmission in the brain. This is important because both excitatory and inhibitory regulation of physiology are important extrinsic factors in the operation of neurons which occur in conjunction with their intrinsic properties. By not taking into account how corticotropin releasing factor affects these processes, a complete picture of this peptide's role in brain function is not available. In this chapter, the limited body of research which has explicitly investigated how corticotropin releasing factor affects excitatory synaptic transmission in various brain regions will be explored.
Topics: Animals; Brain; Corticotropin-Releasing Hormone; Mammals; Stress, Physiological; Synaptic Transmission
PubMed: 32723550
DOI: 10.1016/bs.vh.2020.04.003 -
Glia Nov 2017Astrocytes, a major type of glia, reciprocally influence synaptic transmission and connectivity, forming the "tripartite synapses". Astrocytic metabotropic glutamate... (Review)
Review
Astrocytes, a major type of glia, reciprocally influence synaptic transmission and connectivity, forming the "tripartite synapses". Astrocytic metabotropic glutamate receptor (mGluR)-mediated Ca waves and release of gliotransmitters or synaptogenic molecules mediate this neuron-glia interaction in the developing brain, but this signaling has been challenged for adult brain. However, cumulative evidence has suggested that mature astrocytes exhibit re-awakening of such immature phenotype in the pathological adult brain. This phenotypic change in astrocytes in response to injury may induce neural circuit and synapse plasticity. In this review article, we summarize astrocyte-mediated synapse remodeling during physiological development, discuss re-emergence of immature astrocytic signaling in adult pathological brain, and finally highlight its contribution to significant modification of synaptic connections correlating with functional progress of brain pathology.
Topics: Animals; Astrocytes; Brain; Humans; Synapses; Synaptic Transmission
PubMed: 28569048
DOI: 10.1002/glia.23169 -
Current Opinion in Neurobiology Aug 2022Dysregulation of glutamatergic synapses plays an important role in the pathogenesis of neurological diseases. In addition to mediating excitatory synaptic transmission,... (Review)
Review
Dysregulation of glutamatergic synapses plays an important role in the pathogenesis of neurological diseases. In addition to mediating excitatory synaptic transmission, postsynaptic glutamate receptors interact with various membrane and intracellular proteins. They form structural and/or signaling synaptic protein complexes and thereby play diverse postsynaptic functions. Recently, several postsynaptic protein complexes have been associated with various neurological diseases and hence, have been characterized as important therapeutic targets. Moreover, novel small molecules and therapeutic peptides targeting and modulating the activities of these protein complexes have been discovered, some of which have advanced through preclinical translational research and/or clinical studies. This article describes the recent investigation of eight key protein complexes associated with the postsynaptic ionotropic and metabotropic glutamate receptors as therapeutic targets for central nervous system diseases.
Topics: Receptors, Glutamate; Receptors, Metabotropic Glutamate; Synapses; Synaptic Transmission
PubMed: 35738196
DOI: 10.1016/j.conb.2022.102585 -
Pharmacology & Therapeutics Jan 2019Synaptic transmission is a fundamental neurobiological process enabling exchange of signals between neurons as well as neurons and their non-neuronal effectors. The... (Review)
Review
Synaptic transmission is a fundamental neurobiological process enabling exchange of signals between neurons as well as neurons and their non-neuronal effectors. The complex molecular machinery of the synaptic vesicle cycle and transmitter release has emerged and developed in the course of the evolutionary race, to ensure adaptive gain and survival of the fittest. In parallel, a generous arsenal of biomolecules and neuroactive peptides have co-evolved, which selectively target the transmitter release machinery, with the aim of subduing natural rivals or neutralizing prey. With advances in neuropharmacology and quantitative biology, neurotoxins targeting presynaptic mechanisms have attracted major interest, revealing considerable potential as carriers of molecular cargo and probes for meddling synaptic transmission mechanisms for research and medical benefit. In this review, we investigate and discuss key facets employed by the most prominent bacterial and animal toxins targeting the presynaptic secretory machinery. We explore the cellular basis and molecular grounds for their tremendous potency and selectivity, with effects on a wide range of neural functions. Finally, we consider the emerging preclinical and clinical data advocating the use of active ingredients of neurotoxins for the advancement of molecular medicine and development of restorative therapies.
Topics: Animals; Humans; Neurotoxins; Neurotransmitter Agents; Synaptic Transmission; Toxins, Biological
PubMed: 30149105
DOI: 10.1016/j.pharmthera.2018.08.016 -
Journal of Molecular Medicine (Berlin,... Sep 2015The transient receptor potential (TRPC) proteins form non-selective cation channels that are activated downstream of Gq-phospholipase C-coupled receptors. TRPC3, one of... (Review)
Review
The transient receptor potential (TRPC) proteins form non-selective cation channels that are activated downstream of Gq-phospholipase C-coupled receptors. TRPC3, one of the seven members of the TRPC subfamily, combines functions of an unspecific ion channel and a signal transducer. In the mammalian brain, the expression of TRPC3 is highest in cerebellar Purkinje cells, the principal neurons, and the sole output of the cerebellar cortex. In this review, we summarize findings identifying TRPC3 channels as integral components of glutamatergic metabotropic synaptic transmission. We give an overview of postsynaptic interaction partners and activation mechanisms of TRPC3 in central neurons. Finally, we address the deleterious consequences of distorted TRPC3 synaptic signaling for cerebellar function in different mouse models and present TRPC3 as an emerging candidate protein implicated in various forms of ataxia in humans.
Topics: Animals; Brain; Humans; Neurons; Signal Transduction; Synaptic Transmission; TRPC Cation Channels
PubMed: 26041382
DOI: 10.1007/s00109-015-1298-7 -
IEEE Transactions on Nanobioscience Apr 2023In synaptic molecular communication (MC), the activation of postsynaptic receptors by neurotransmitter (NTs) is governed by a stochastic reaction-diffusion process. This...
In synaptic molecular communication (MC), the activation of postsynaptic receptors by neurotransmitter (NTs) is governed by a stochastic reaction-diffusion process. This randomness of synaptic MC contributes to the randomness of the electrochemical downstream signal in the postsynaptic cell, called postsynaptic membrane potential (PSP). Since the randomness of the PSP is relevant for neural computation and learning, characterizing the statistics of the PSP is critical. However, the statistical characterization of the synaptic reaction-diffusion process is difficult because the reversible bi-molecular reaction of NTs with receptors renders the system nonlinear. Consequently, there is currently no model available which characterizes the impact of the statistics of postsynaptic receptor activation on the PSP. In this work, we propose a novel statistical model for the synaptic reaction-diffusion process in terms of the chemical master equation (CME). We further propose a novel numerical method which allows to compute the CME efficiently and we use this method to characterize the statistics of the PSP. Finally, we present results from stochastic particle-based computer simulations which validate the proposed models. We show that the biophysical parameters governing synaptic transmission shape the autocovariance of the receptor activation and, ultimately, the statistics of the PSP. Our results suggest that the processing of the synaptic signal by the postsynaptic cell effectively mitigates synaptic noise while the statistical characteristics of the synaptic signal are preserved. The results presented in this paper contribute to a better understanding of the impact of the randomness of synaptic signal transmission on neuronal information processing.
Topics: Synaptic Transmission; Neurons; Computer Simulation; Models, Statistical; Neurotransmitter Agents; Synapses; Models, Neurological
PubMed: 35709120
DOI: 10.1109/TNB.2022.3183692 -
Synapse (New York, N.Y.) Oct 2019Extracellular pH changes may constitute significant signals for neuronal communication. During synaptic transmission, changes in pH in the synaptic cleft take place. Its... (Review)
Review
Extracellular pH changes may constitute significant signals for neuronal communication. During synaptic transmission, changes in pH in the synaptic cleft take place. Its role in the regulation of presynaptic Ca currents through multivesicular release in ribbon-type synapses is a proven phenomenon. In recent years, protons have been recognized as neurotransmitters that participate in neuronal communication in synapses of several regions of the CNS such as amygdala, nucleus accumbens, and brainstem. Protons are released by nerve stimulation and activate postsynaptic acid-sensing ion channels (ASICs). Several types of ASIC channels are expressed in the peripheral and central nervous system. The influx of Ca through some subtypes of ASICs, as a result of synaptic transmission, agrees with the participation of ASICs in synaptic plasticity. Pharmacological and genetical inhibition of ASIC1a results in alterations in learning, memory, and phenomena like fear and cocaine-seeking behavior. The recognition of endogenous molecules, such as arachidonic acid, cytokines, histamine, spermine, lactate, and neuropeptides, capable of inhibiting or potentiating ASICs suggests the existence of mechanisms of synaptic modulation that have not yet been fully identified and that could be tuned by new emerging pharmacological compounds with potential therapeutic benefits.
Topics: Acid Sensing Ion Channels; Animals; Brain; Humans; Protons; Synaptic Transmission
PubMed: 31180161
DOI: 10.1002/syn.22120