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Nature Neuroscience Mar 2020Emerging evidence indicates that liquid-liquid phase separation, the formation of a condensed molecular assembly within another diluted aqueous solution, is a means for... (Review)
Review
Emerging evidence indicates that liquid-liquid phase separation, the formation of a condensed molecular assembly within another diluted aqueous solution, is a means for cells to organize highly condensed biological assemblies (also known as biological condensates or membraneless compartments) with very broad functions and regulatory properties in different subcellular regions. Molecular machineries dictating synaptic transmissions in both presynaptic boutons and postsynaptic densities of neuronal synapses may be such biological condensates. Here we review recent developments showing how phase separation can build dense synaptic molecular clusters, highlight unique features of such condensed clusters in the context of synaptic development and signaling, discuss how aberrant phase-separation-mediated synaptic assembly formation may contribute to dysfunctional signaling in psychiatric disorders, and present some challenges and opportunities of phase separation in synaptic biology.
Topics: Animals; Humans; Post-Synaptic Density; Presynaptic Terminals; Synapses; Synaptic Transmission
PubMed: 32015539
DOI: 10.1038/s41593-019-0579-9 -
International Journal of Molecular... May 2019Presynaptic Ca entry occurs through voltage-gated Ca (Ca) channels which are activated by membrane depolarization. Depolarization accompanies neuronal firing and... (Review)
Review
Presynaptic Ca entry occurs through voltage-gated Ca (Ca) channels which are activated by membrane depolarization. Depolarization accompanies neuronal firing and elevation of Ca triggers neurotransmitter release from synaptic vesicles. For synchronization of efficient neurotransmitter release, synaptic vesicles are targeted by presynaptic Ca channels forming a large signaling complex in the active zone. The presynaptic Ca2 channel gene family (comprising Ca2.1, Ca2.2, and Ca2.3 isoforms) encode the pore-forming α1 subunit. The cytoplasmic regions are responsible for channel modulation by interacting with regulatory proteins. This article overviews modulation of the activity of Ca2.1 and Ca2.2 channels in the control of synaptic strength and presynaptic plasticity.
Topics: Animals; Calcium Channels, N-Type; Calcium-Binding Proteins; Humans; Presynaptic Terminals; Synaptic Potentials
PubMed: 31064106
DOI: 10.3390/ijms20092217 -
Neuroscience Research Feb 2018At the presynaptic terminal, neuronal firing activity induces membrane depolarization and subsequent Ca entry through voltage-gated Ca (Ca) channels triggers... (Review)
Review
At the presynaptic terminal, neuronal firing activity induces membrane depolarization and subsequent Ca entry through voltage-gated Ca (Ca) channels triggers neurotransmitter release from the active zone. Presynaptic Ca channels form a large signaling complex, which targets synaptic vesicles to Ca channels for efficient release and mediates Ca channel regulation. The presynaptic Ca2 channel family (comprising Ca2.1, Ca2.2 and Ca2.3 isoforms) encode the pore-forming α1 subunit. The cytoplasmic regions are the target of regulatory proteins for channel modulation. Modulation of presynaptic Ca channels has a powerful influence on synaptic transmission. This article overviews spatial and temporal regulation of Ca channels by effectors and sensors of Ca signaling, and describes the emerging evidence for a critical role of Ca channel regulation in control of synaptic transmission and presynaptic plasticity. Sympathetic superior cervical ganglion neurons in culture expressing Ca2.2 channels represent a well-characterized system for investigating synaptic transmission. The exogenously expressed α1 subunit of the Ca2.1 as well as endogenous Ca2.2 was examined for modulation of channel activity, and thereby regulation of synaptic transmission. The constitutive and Ca-dependent modulation of Ca2.1 channels coordinately act as spatial and temporal molecular switches to control synaptic efficacy.
Topics: Animals; Calcium; Calcium Channels; Humans; Models, Molecular; Neurons; Presynaptic Terminals; Synaptic Transmission
PubMed: 29317246
DOI: 10.1016/j.neures.2017.09.012 -
Cell Calcium Jan 2020Synaptic transmission relies on rapid calcium (Ca) influx into presynaptic terminal via voltage-gated Ca channels. However, smooth ER is present in presynaptic terminals... (Review)
Review
Synaptic transmission relies on rapid calcium (Ca) influx into presynaptic terminal via voltage-gated Ca channels. However, smooth ER is present in presynaptic terminals and accumulating evidence indicate that ER Ca signaling may play a modulatory role in synaptic transmission. Most recent publication by Lindhout and colleagues (EMBO J, 38 (2019) e101345) suggested that the fragmentation state of the ER affects synaptic vesicle release. Here we discuss these results as well as several key publications that addressed a connection between ER Ca signaling and synaptic transmission.
Topics: Animals; Calcium; Endoplasmic Reticulum; Humans; Models, Biological; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 31812114
DOI: 10.1016/j.ceca.2019.102133 -
International Journal of Molecular... Mar 2022The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors. To meet these energetic... (Review)
Review
The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors. To meet these energetic requirements, the brain primarily uses glucose, which can be metabolized through glycolysis and/or mitochondrial oxidative phosphorylation. The relevance of these two energy production pathways in fulfilling energy at presynaptic terminals has been the subject of recent studies. In this review, we dissect the balance of glycolysis and oxidative phosphorylation to meet synaptic energy demands in both resting and stimulation conditions. Besides ATP output needs, mitochondria at synapse are also important for calcium buffering and regulation of reactive oxygen species. These two mitochondrial-associated pathways, once hampered, impact negatively on neuronal homeostasis and synaptic activity. Therefore, as mitochondria assume a critical role in synaptic homeostasis, it is becoming evident that the synaptic mitochondria population possesses a distinct functional fingerprint compared to other brain mitochondria. Ultimately, dysregulation of synaptic bioenergetics through glycolytic and mitochondrial dysfunctions is increasingly implicated in neurodegenerative disorders, as one of the first hallmarks in several of these diseases are synaptic energy deficits, followed by synapse degeneration.
Topics: Animals; Brain; Energy Metabolism; Mammals; Presynaptic Terminals; Synapses; Synaptic Transmission
PubMed: 35408993
DOI: 10.3390/ijms23073627 -
Current Opinion in Neurobiology Feb 2019Plastic changes in synaptic transmission are thought to underlie learning and memory formation. However, changes in synaptic function are only meaningful in the context... (Review)
Review
Plastic changes in synaptic transmission are thought to underlie learning and memory formation. However, changes in synaptic function are only meaningful in the context of stable baseline function. Accumulating evidence suggests that homeostatic signaling systems actively stabilize synaptic transmission in response to neural activity perturbation. Homeostatic mechanisms control both presynaptic and postsynaptic function. Here, we review recent advances in the field of presynaptic homeostatic plasticity (PHP). We discuss PHP in the context of basic mechanisms controlling neurotransmitter release, highlight emerging similarities between different synapses in different species, and summarize new insights into the molecular mechanisms underlying this evolutionary conserved form of synaptic plasticity.
Topics: Animals; Homeostasis; Neuronal Plasticity; Presynaptic Terminals; Signal Transduction
PubMed: 30384022
DOI: 10.1016/j.conb.2018.10.003 -
Neuron Aug 2022Learning and memory rely on long-lasting, synapse-specific modifications. Although postsynaptic forms of plasticity typically require local protein synthesis, whether...
Learning and memory rely on long-lasting, synapse-specific modifications. Although postsynaptic forms of plasticity typically require local protein synthesis, whether and how local protein synthesis contributes to presynaptic changes remain unclear. Here, we examined the mouse hippocampal mossy fiber (MF)-CA3 synapse, which expresses both structural and functional presynaptic plasticity and contains presynaptic fragile X messenger ribonucleoprotein (FMRP), an RNA-binding protein involved in postsynaptic protein-synthesis-dependent plasticity. We report that MF boutons contain ribosomes and synthesize protein locally. The long-term potentiation of MF-CA3 synaptic transmission (MF-LTP) was associated with the translation-dependent enlargement of MF boutons. Remarkably, increasing in vitro or in vivo MF activity enhanced the protein synthesis in MFs. Moreover, the deletion of presynaptic FMRP blocked structural and functional MF-LTP, suggesting that FMRP is a critical regulator of presynaptic MF plasticity. Thus, presynaptic FMRP and protein synthesis dynamically control presynaptic structure and function in the mature mammalian brain.
Topics: Animals; Fragile X Mental Retardation Protein; Long-Term Potentiation; Mammals; Mice; Mossy Fibers, Hippocampal; Neuronal Plasticity; Presynaptic Terminals; Ribonucleoproteins; Synapses
PubMed: 35728596
DOI: 10.1016/j.neuron.2022.05.024 -
Journal of Neurochemistry Dec 2016Proper brain function in the nervous system relies on the accurate establishment of synaptic contacts during development. Countless synapses populate the adult brain in... (Review)
Review
Proper brain function in the nervous system relies on the accurate establishment of synaptic contacts during development. Countless synapses populate the adult brain in an orderly fashion. In each synapse, a presynaptic terminal loaded with neurotransmitters-containing synaptic vesicles is perfectly aligned to an array of receptors in the postsynaptic membrane. Presynaptic differentiation, which encompasses the events underlying assembly of new presynaptic units, has seen notable advances in recent years. It is now consensual that as a growing axon encounters the receptive dendrites of its partner, presynaptic assembly will be triggered and specified by multiple postsynaptically-derived factors including soluble molecules and cell adhesion complexes. Presynaptic material that reaches these distant sites by axonal transport in the form of pre-assembled packets will be retained and clustered, ultimately giving rise to a presynaptic bouton. This review focuses on the cellular and molecular aspects of presynaptic differentiation in the central nervous system, with a particular emphasis on the identity of the instructive factors and the intracellular processes used by neuronal cells to assemble functional presynaptic terminals. We provide a detailed description of the mechanisms leading to the formation of new presynaptic terminals. In brief, soma-derived packets of pre-assembled material are trafficked to distant axonal sites. Synaptogenic factors from dendritic or glial provenance activate downstream intra-axonal mediators to trigger clustering of passing material and their correct organization into a new presynaptic bouton. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".
Topics: Animals; Axons; Cell Differentiation; Dendrites; Humans; Presynaptic Terminals; Synapses
PubMed: 27315450
DOI: 10.1111/jnc.13702 -
Alcoholism, Clinical and Experimental... Jan 2020Alcohol addiction causes major health problems throughout the world, causing numerous deaths and incurring a huge economic burden to society. To develop an intervention... (Review)
Review
Alcohol addiction causes major health problems throughout the world, causing numerous deaths and incurring a huge economic burden to society. To develop an intervention for alcohol addiction, it is necessary to identify molecular target(s) of alcohol and associated molecular mechanisms of alcohol action. The functions of many central and peripheral synapses are impacted by low concentrations of ethanol (EtOH). While the postsynaptic targets and mechanisms are studied extensively, there are limited studies on the presynaptic targets and mechanisms. This article is an endeavor in this direction, focusing on the effect of EtOH on the presynaptic proteins associated with the neurotransmitter release machinery. Studies on the effects of EtOH at the levels of gene, protein, and behavior are highlighted in this article.
Topics: Alcoholism; Animals; Ethanol; Humans; Presynaptic Terminals; Protein Structure, Secondary; Protein Structure, Tertiary; SNARE Proteins; Synapses; Synaptic Transmission
PubMed: 31724225
DOI: 10.1111/acer.14238 -
Function (Oxford, England) 2021Voltage-gated calcium channels are the principal conduits for depolarization-mediated Ca entry into excitable cells. In this review, the biophysical properties of the... (Review)
Review
Voltage-gated calcium channels are the principal conduits for depolarization-mediated Ca entry into excitable cells. In this review, the biophysical properties of the relevant members of this family of channels, those that are present in presynaptic terminals, will be discussed in relation to their function in mediating neurotransmitter release. Voltage-gated calcium channels have properties that ensure they are specialized for particular roles, for example, differences in their activation voltage threshold, their various kinetic properties, and their voltage-dependence of inactivation. All these attributes play into the ability of the various voltage-gated calcium channels to participate in different patterns of presynaptic vesicular release. These include synaptic transmission resulting from single action potentials, and longer-term changes mediated by bursts or trains of action potentials, as well as release resulting from graded changes in membrane potential in specialized sensory synapses.
Topics: Presynaptic Terminals; Calcium Channels; Synaptic Transmission; Synapses; Action Potentials
PubMed: 33313507
DOI: 10.1093/function/zqaa027