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Molecular Pain 2020Extracellular signal-regulated kinases are widely expressed protein kinases in neurons, which serve as important intracellular signaling molecules for central plasticity... (Review)
Review
Extracellular signal-regulated kinases are widely expressed protein kinases in neurons, which serve as important intracellular signaling molecules for central plasticity such as long-term potentiation. Recent studies demonstrate that there are two major forms of long-term potentiation in cortical areas related to pain: postsynaptic long-term potentiation and presynaptic long-term potentiation. In particular, presynaptic long-term potentiation in the anterior cingulate cortex has been shown to contribute to chronic pain-related anxiety. In this review, we briefly summarized the components and roles of extracellular signal-regulated kinases in neuronal signaling, especially in the presynaptic long-term potentiation of anterior cingulate cortex, and discuss the possible molecular mechanisms and functional implications in pain-related emotional disorders.
Topics: Acute Pain; Animals; Chronic Pain; Excitatory Postsynaptic Potentials; Extracellular Signal-Regulated MAP Kinases; Gyrus Cinguli; Hippocampus; Humans; Learning; Long-Term Potentiation; MAP Kinase Signaling System; Neurons; Presynaptic Terminals; Signal Transduction; Synapses
PubMed: 32264746
DOI: 10.1177/1744806920917245 -
Cells Aug 2019Although acetylcholine is the major neurotransmitter operating at the skeletal neuromuscular junction of many invertebrates and of vertebrates, glutamate participates in... (Review)
Review
Although acetylcholine is the major neurotransmitter operating at the skeletal neuromuscular junction of many invertebrates and of vertebrates, glutamate participates in modulating cholinergic transmission and plastic changes in the last. Presynaptic terminals of neuromuscular junctions contain and release glutamate that contribute to the regulation of synaptic neurotransmission through its interaction with pre- and post-synaptic receptors activating downstream signaling pathways that tune synaptic efficacy and plasticity. During vertebrate development, the chemical nature of the neurotransmitter at the vertebrate neuromuscular junction can be experimentally shifted from acetylcholine to other mediators (including glutamate) through the modulation of calcium dynamics in motoneurons and, when the neurotransmitter changes, the muscle fiber expresses and assembles new receptors to match the nature of the new mediator. Finally, in adult rodents, by diverting descending spinal glutamatergic axons to a denervated muscle, a functional reinnervation can be achieved with the formation of new neuromuscular junctions that use glutamate as neurotransmitter and express ionotropic glutamate receptors and other markers of central glutamatergic synapses. Here, we summarize the past and recent experimental evidences in support of a role of glutamate as a mediator at the synapse between the motor nerve ending and the skeletal muscle fiber, focusing on the molecules and signaling pathways that are present and activated by glutamate at the vertebrate neuromuscular junction.
Topics: Acetylcholine; Animals; Calcium; Glutamic Acid; Humans; Membrane Transport Proteins; Mice; Motor Neurons; Muscle Fibers, Skeletal; Neuromuscular Junction; Presynaptic Terminals; Rats; Receptors, Neurotransmitter; Synaptic Transmission
PubMed: 31466388
DOI: 10.3390/cells8090996 -
Movement Disorders : Official Journal... Sep 2022Imaging tools that allow quantification of Parkinson's disease (PD) progression could facilitate the development of disease-modifying therapies. Cross-sectional studies...
BACKGROUND
Imaging tools that allow quantification of Parkinson's disease (PD) progression could facilitate the development of disease-modifying therapies. Cross-sectional studies have shown presynaptic terminal damage in PD patients, but longitudinal data are limited.
OBJECTIVES
The aim of this study was to longitudinally assess loss of presynaptic terminals in general and dopaminergic presynaptic terminals in particular as measures of disease progression in early PD.
METHODS
A total of 27 patients with early PD and 18 age- and sex-matched healthy controls underwent positron emission tomography (PET) with C-UCB-J, a ligand for the brain-wide presynaptic terminal marker SV2A, and with F-FE-PE2I, a highly selective dopamine transporter ligand, in combination with a comprehensive motor and non-motor clinical assessment at baseline (BL) and after 26.5 ± 2.1 months (Y2). SUVR-1 images were calculated and volumes of interest were delineated based on individual 3D T1 magnetic resonance imaging (MRI).
RESULTS
PD patients showed significant 2-year worsening of Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) (off medication) scores, but not of non-motor scores. Motor and non-motor scores in controls did not change significantly over 2 years. F-FE-PE2I binding in caudate and putamen showed significant 2-year decline in the PD group and remained unchanged in controls. Longitudinal decline of striatal F-FE-PE2I binding in PD did not correlate with longitudinal changes in MDS-UPDRS-III scores. C-UCB-J PET did not show any region with significant 2-year change in PD or controls.
CONCLUSIONS
F-FE-PE2I PET showed robust 2-year decline in early PD, but C-UCB-J PET did not. Longitudinal changes in F-FE-PE2I binding did not correlate with clinical motor progression. © 2022 International Parkinson and Movement Disorder Society.
Topics: Cross-Sectional Studies; Humans; Ligands; Parkinson Disease; Positron-Emission Tomography; Presynaptic Terminals
PubMed: 35819412
DOI: 10.1002/mds.29148 -
Neuroscience Mar 2021Nearly sixty years ago Fredrich Timm developed a histochemical technique that revealed a rich reserve of free zinc in distinct regions of the brain. Subsequent electron... (Review)
Review
Nearly sixty years ago Fredrich Timm developed a histochemical technique that revealed a rich reserve of free zinc in distinct regions of the brain. Subsequent electron microscopy studies in Timm- stained brain tissue found that this "labile" pool of cellular zinc was highly concentrated at synaptic boutons, hinting a possible role for the metal in synaptic transmission. Although evidence for activity-dependent synaptic release of zinc would not be reported for another twenty years, these initial findings spurred decades of research into zinc's role in neuronal function and revealed a diverse array of signaling cascades triggered or regulated by the metal. Here, we delve into our current understanding of the many roles zinc plays in the brain, from influencing neurotransmission and sensory processing, to activating both pro-survival and pro-death neuronal signaling pathways. Moreover, we detail the many mechanisms that tightly regulate cellular zinc levels, including metal binding proteins and a large array of zinc transporters.
Topics: Brain; Neurons; Presynaptic Terminals; Synaptic Transmission; Zinc
PubMed: 33460731
DOI: 10.1016/j.neuroscience.2021.01.010 -
Neuron Jun 2021Optical manipulations of genetically defined cell types have generated significant insights into the dynamics of neural circuits. While optogenetic activation has been...
Optical manipulations of genetically defined cell types have generated significant insights into the dynamics of neural circuits. While optogenetic activation has been relatively straightforward, rapid and reversible synaptic inhibition has proven more elusive. Here, we leveraged the natural ability of inhibitory presynaptic GPCRs to suppress synaptic transmission and characterize parapinopsin (PPO) as a GPCR-based opsin for terminal inhibition. PPO is a photoswitchable opsin that couples to G signaling cascades and is rapidly activated by pulsed blue light, switched off with amber light, and effective for repeated, prolonged, and reversible inhibition. PPO rapidly and reversibly inhibits glutamate, GABA, and dopamine release at presynaptic terminals. Furthermore, PPO alters reward behaviors in a time-locked and reversible manner in vivo. These results demonstrate that PPO fills a significant gap in the neuroscience toolkit for rapid and reversible synaptic inhibition and has broad utility for spatiotemporal control of inhibitory GPCR signaling cascades.
Topics: Animals; Dopamine; Exocytosis; Fish Proteins; Glutamic Acid; HEK293 Cells; HeLa Cells; Humans; Male; Mice; Neural Inhibition; Optogenetics; Presynaptic Terminals; Receptors, G-Protein-Coupled; Reward; Rod Opsins; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 33979635
DOI: 10.1016/j.neuron.2021.04.026 -
Neuron Mar 2021Tau is a major driver of neurodegeneration and is implicated in over 20 diseases. Tauopathies are characterized by synaptic loss and neuroinflammation, but it is unclear...
Tau is a major driver of neurodegeneration and is implicated in over 20 diseases. Tauopathies are characterized by synaptic loss and neuroinflammation, but it is unclear if these pathological events are causally linked. Tau binds to Synaptogyrin-3 on synaptic vesicles. Here, we interfered with this function to determine the role of pathogenic Tau at pre-synaptic terminals. We show that heterozygous knockout of synaptogyrin-3 is benign in mice but strongly rescues mutant Tau-induced defects in long-term synaptic plasticity and working memory. It also significantly rescues the pre- and post-synaptic loss caused by mutant Tau. However, Tau-induced neuroinflammation remains clearly upregulated when we remove the expression of one allele of synaptogyrin-3. Hence neuroinflammation is not sufficient to cause synaptic loss, and these processes are separately induced in response to mutant Tau. In addition, the pre-synaptic defects caused by mutant Tau are enough to drive defects in cognitive tasks.
Topics: Animals; Encephalitis; Female; Hippocampus; Male; Memory Disorders; Mice, Knockout; Microglia; Neuronal Plasticity; Presynaptic Terminals; Synaptogyrins; tau Proteins; Mice
PubMed: 33472038
DOI: 10.1016/j.neuron.2020.12.016 -
The Journal of Neuroscience : the... Mar 2022Efficient and reliable neurotransmission requires precise coupling between action potentials (APs), Ca entry and neurotransmitter release. However, Ca requirements for...
Efficient and reliable neurotransmission requires precise coupling between action potentials (APs), Ca entry and neurotransmitter release. However, Ca requirements for release, including the number of channels required, their subtypes, and their location with respect to primed vesicles, remains to be precisely defined for central synapses. Indeed, Ca entry may occur through small numbers or even single open Ca channels, but these questions remain largely unexplored in simple active zone (AZ) synapses common in the nervous system, and key to addressing Ca channel and synaptic dysfunction underlying numerous neurologic and neuropsychiatric disorders. Here, we present single channel analysis of evoked AZ Ca entry, using cell-attached patch clamp and lattice light-sheet microscopy (LLSM), resolving small channel numbers evoking Ca entry following depolarization, at single AZs in individual central lamprey reticulospinal presynaptic terminals from male and females. We show a small pool (mean of 23) of Ca channels at each terminal, comprising N-(CaV2.2), P/Q-(CaV2.1), and R-(CaV2.3) subtypes, available to gate neurotransmitter release. Significantly, of this pool only one to seven channels (mean of 4) open on depolarization. High temporal fidelity lattice light-sheet imaging reveals AP-evoked Ca transients exhibiting quantal amplitude variations of 0-6 event sizes between individual APs and stochastic variation of precise locations of Ca entry within the AZ. Further, total Ca channel numbers at each AZ correlate to the number of presynaptic primed synaptic vesicles. Dispersion of channel openings across the AZ and the similar number of primed vesicles and channels indicate that Ca entry via as few as one channel may trigger neurotransmitter release. Presynaptic Ca entry through voltage-gated calcium channels (VGCCs) causes neurotransmitter release. To understand neurotransmission, its modulation, and plasticity, we must quantify Ca entry and its relationship to vesicle fusion. This requires direct recordings from active zones (AZs), previously possible only at calyceal terminals containing many AZs, where few channels open following action potentials (APs; Sheng et al., 2012), and even single channel openings may trigger release (Stanley, 1991, 1993). However, recording from more conventional terminals with single AZs commonly found centrally has thus far been impossible. We addressed this by cell-attached recordings from acutely dissociated single lamprey giant axon AZs, and by lattice light sheet microscopy of presynaptic Ca entry. We demonstrate nanodomains of presynaptic VGCCs coupling with primed vesicles with 1:1 stoichiometry.
Topics: Animals; Calcium; Female; Lampreys; Male; Neurotransmitter Agents; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 35063999
DOI: 10.1523/JNEUROSCI.2207-21.2022 -
PLoS Biology Dec 2023Neuronal development orchestrates the formation of an enormous number of synapses that connect the nervous system. In developing presynapses, the core active zone...
Neuronal development orchestrates the formation of an enormous number of synapses that connect the nervous system. In developing presynapses, the core active zone structure has been found to assemble through liquid-liquid phase separation. Here, we find that the phase separation of Caenorhabditis elegans SYD-2/Liprin-α, a key active zone scaffold, is controlled by phosphorylation. We identify the SAD-1 kinase as a regulator of SYD-2 phase separation and determine presynaptic assembly is impaired in sad-1 mutants and increased by overactivation of SAD-1. Using phosphoproteomics, we find SAD-1 phosphorylates SYD-2 on 3 sites that are critical to activate phase separation. Mechanistically, SAD-1 phosphorylation relieves a binding interaction between 2 folded domains in SYD-2 that inhibits phase separation by an intrinsically disordered region (IDR). We find synaptic cell adhesion molecules localize SAD-1 to nascent synapses upstream of active zone formation. We conclude that SAD-1 phosphorylates SYD-2 at developing synapses, activating its phase separation and active zone assembly.
Topics: Animals; Presynaptic Terminals; Caenorhabditis elegans Proteins; Synapses; Caenorhabditis elegans; Intercellular Signaling Peptides and Proteins
PubMed: 38048304
DOI: 10.1371/journal.pbio.3002421 -
Movement Disorders : Official Journal... Oct 2019While current effective therapies are available for the symptomatic control of PD, treatments to halt the progressive neurodegeneration still do not exist. Loss of... (Review)
Review
While current effective therapies are available for the symptomatic control of PD, treatments to halt the progressive neurodegeneration still do not exist. Loss of dopamine neurons in the SNc and dopamine terminals in the striatum drive the motor features of PD. Multiple lines of research point to several pathways which may contribute to dopaminergic neurodegeneration. These pathways include extensive axonal arborization, mitochondrial dysfunction, dopamine's biochemical properties, abnormal protein accumulation of α-synuclein, defective autophagy and lysosomal degradation, and synaptic impairment. Thus, understanding the essential features and mechanisms of dopaminergic neuronal vulnerability is a major scientific challenge and highlights an outstanding need for fostering effective therapies against neurodegeneration in PD. This article, which arose from the Movement Disorders 2018 Conference, discusses and reviews the possible mechanisms underlying neuronal vulnerability and potential therapeutic approaches in PD. © 2019 International Parkinson and Movement Disorder Society.
Topics: Animals; Axons; Chromosome Pairing; Dopaminergic Neurons; Humans; Parkinson Disease; Parkinsonian Disorders; Presynaptic Terminals
PubMed: 31483900
DOI: 10.1002/mds.27823 -
Cells Mar 2021In presynaptic terminals, synaptic vesicles (SVs) are found in a discrete cluster that includes a reserve pool that is mobilized during synaptic activity. Synapsins... (Review)
Review
In presynaptic terminals, synaptic vesicles (SVs) are found in a discrete cluster that includes a reserve pool that is mobilized during synaptic activity. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. Here, we summarize what is known about the role of synapsins in clustering of SVs and evaluate experimental evidence supporting these two models.
Topics: Animals; Exocytosis; Humans; Models, Neurological; Presynaptic Terminals; Protein Binding; Protein Transport; Synapsins; Synaptic Transmission; Synaptic Vesicles
PubMed: 33809712
DOI: 10.3390/cells10030658