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Biomolecules Mar 2022α-synuclein (α-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson's disease (PD), dementia with Lewy bodies... (Review)
Review
α-synuclein (α-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Alzheimer's Disease (AD). In normal physiology, α-syn plays a pivotal role in facilitating endocytosis and exocytosis. Interestingly, mutations and modifications of precise α-syn domains interfere with α-syn oligomerization and nucleation that negatively affect presynaptic vesicular dynamics, protein expressions, and mitochondrial profiles. Furthermore, the integration of the α-syn oligomers into the presynaptic membrane results in pore formations, ion influx, and excitotoxicity. Targeted therapies against specific domains of α-syn, including the use of small organic molecules, monoclonal antibodies, and synthetic peptides, are being screened and developed. However, the prospect of an effective α-syn targeted therapy is still plagued by low permeability across the blood-brain barrier (BBB), and poor entry into the presynaptic axon terminals. The present review proposes a modification of current strategies, which includes the use of novel encapsulation technology, such as lipid nanoparticles, to bypass the BBB and deliver such agents into the brain.
Topics: Humans; Liposomes; Nanoparticles; Parkinson Disease; Presynaptic Terminals; alpha-Synuclein
PubMed: 35454096
DOI: 10.3390/biom12040507 -
Learning & Memory (Cold Spring Harbor,... May 2024The intricate molecular and structural sequences guiding the formation and consolidation of memories within neuronal circuits remain largely elusive. In this study, we...
The intricate molecular and structural sequences guiding the formation and consolidation of memories within neuronal circuits remain largely elusive. In this study, we investigate the roles of two pivotal presynaptic regulators, the small GTPase Rab3, enriched at synaptic vesicles, and the cell adhesion protein Neurexin-1, in the formation of distinct memory phases within the mushroom body Kenyon cells. Our findings suggest that both proteins play crucial roles in memory-supporting processes within the presynaptic terminal, operating within distinct plasticity modules. These modules likely encompass remodeling and maturation of existing active zones (AZs), as well as the formation of new AZs.
Topics: Animals; Mushroom Bodies; Presynaptic Terminals; Drosophila Proteins; Memory; rab3 GTP-Binding Proteins; Nerve Tissue Proteins; Drosophila; Synaptic Vesicles
PubMed: 38862173
DOI: 10.1101/lm.054013.124 -
Neuron Nov 2017At each of the brain's vast number of synapses, the presynaptic nerve terminal, synaptic cleft, and postsynaptic specialization form a transcellular unit to enable... (Review)
Review
At each of the brain's vast number of synapses, the presynaptic nerve terminal, synaptic cleft, and postsynaptic specialization form a transcellular unit to enable efficient transmission of information between neurons. While we know much about the molecular machinery within each compartment, we are only beginning to understand how these compartments are structurally registered and functionally integrated with one another. This review will describe the organization of each compartment and then discuss their alignment across pre- and postsynaptic cells at a nanometer scale. We propose that this architecture may allow for precise synaptic information exchange and may be modulated to contribute to the remarkable plasticity of brain function.
Topics: Animals; Cell Communication; Exocytosis; Humans; Neuronal Plasticity; Presynaptic Terminals; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 29096080
DOI: 10.1016/j.neuron.2017.10.006 -
Current Opinion in Neurobiology Aug 2018Presynaptic nerve terminals release neurotransmitter synchronously, asynchronously or spontaneously. During synchronous neurotransmission release is precisely coupled to... (Review)
Review
Presynaptic nerve terminals release neurotransmitter synchronously, asynchronously or spontaneously. During synchronous neurotransmission release is precisely coupled to action potentials, in contrast, asynchronous release events show only loose temporal coupling to presynaptic activity whereas spontaneous neurotransmission occurs independent of presynaptic activity. The mechanisms that give rise to this diversity in neurotransmitter release modes are poorly understood. Recent studies have described several presynaptic molecular pathways controlling synaptic vesicle pool segregation and recycling, which in turn may dictate distinct modes of neurotransmitter release. In this article, we review this recent work regarding neurotransmitter release modes and their relationship to synaptic vesicle pool dynamics as well as the molecular machinery that establishes synaptic vesicle pool identity.
Topics: Action Potentials; Animals; Models, Neurological; Neurons; Neurotransmitter Agents; Presynaptic Terminals; Synaptic Vesicles
PubMed: 29597140
DOI: 10.1016/j.conb.2018.03.005 -
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 -
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 -
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 -
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