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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 -
Nature Nov 2016The effects of Δ-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are... (Review)
Review
The effects of Δ-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid-dopamine interactions that take place, there is conflicting evidence from human and animal studies concerning the effects of THC on the dopamine system. Acute THC administration causes increased dopamine release and neuron activity, whereas long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of THC.
Topics: Animals; Behavior, Animal; Brain; Cell Shape; Dopamine; Dopaminergic Neurons; Dronabinol; Eating; Humans; Post-Synaptic Density; Presynaptic Terminals; Receptor, Cannabinoid, CB1
PubMed: 27853201
DOI: 10.1038/nature20153 -
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 -
Invertebrate Neuroscience : IN Mar 2018Synapses are specialized contact sites that mediate information flow between neurons and their targets. Important physical interactions across the synapse are mediated... (Review)
Review
Synapses are specialized contact sites that mediate information flow between neurons and their targets. Important physical interactions across the synapse are mediated by synaptic adhesion molecules. These adhesions regulate formation of synapses during development and play a role during mature synaptic function. Importantly, genes regulating synaptogenesis and axon regeneration are conserved across the animal phyla. Genetic screens in the nematode Caenorhabditis elegans have identified a number of molecules required for synapse patterning and assembly. C. elegans is able to survive even with its neuronal function severely compromised. This is in comparison with Drosophila and mice where increased complexity makes them less tolerant to impaired function. Although this fact may reflect differences in the function of the homologous proteins in the synapses between these organisms, the most likely interpretation is that many of these components are equally important, but not absolutely essential, for synaptic transmission to support the relatively undemanding life style of laboratory maintained C. elegans. Here, we review research on the major group of synaptic proteins, involved in the presynaptic machinery in C. elegans, showing a strong conservation between higher organisms and highlight how C. elegans can be used as an informative tool for dissecting synaptic components, based on a simple nervous system organization.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Neurons; Presynaptic Terminals; Synapses; Synaptic Transmission
PubMed: 29532181
DOI: 10.1007/s10158-018-0207-5 -
Journal of Alzheimer's Disease : JAD 2024A key aspect of synaptic dysfunction in Alzheimer's disease (AD) is loss of synaptic proteins. Previous publications showed that the presynaptic machinery is more... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A key aspect of synaptic dysfunction in Alzheimer's disease (AD) is loss of synaptic proteins. Previous publications showed that the presynaptic machinery is more strongly affected than postsynaptic proteins. However, it has also been reported that presynaptic protein loss is highly variable and shows region- and protein-specificity.
OBJECTIVE
The objective of this meta-analysis was to provide an update on the available literature and to further characterize patterns of presynaptic protein loss in AD.
METHODS
Systematic literature search was conducted for studies published between 2015-2022 which quantified presynaptic proteins in postmortem tissue from AD patients and healthy controls. Three-level random effects meta-analyses of twenty-two identified studies was performed to characterize overall presynaptic protein loss and changes in specific regions, proteins, protein families, and functional categories.
RESULTS
Meta-analysis confirmed overall loss of presynaptic proteins in AD patients. Subgroup analysis revealed region specificity of protein loss, with largest effects in temporal and frontal cortex. Results concerning different groups of proteins were also highly variable. Strongest and most consistently affected was the family of synaptosome associated proteins, especially SNAP25. Among the most severely affected were proteins regulating dense core vesicle exocytosis and the synaptic vesicle cycle.
CONCLUSIONS
Results confirm previous literature related to presynaptic protein loss in AD patients and provide further in-depth characterization of most affected proteins and presynaptic functions.
Topics: Humans; Alzheimer Disease; Proteins; Presynaptic Terminals
PubMed: 38073390
DOI: 10.3233/JAD-231034 -
Proceedings of the Japan Academy.... 2017For reliable transmission at chemical synapses, neurotransmitters must be released dynamically in response to neuronal activity in the form of action potentials. Stable... (Review)
Review
For reliable transmission at chemical synapses, neurotransmitters must be released dynamically in response to neuronal activity in the form of action potentials. Stable synaptic transmission is dependent on the efficacy of transmitter release and the rate of resupplying synaptic vesicles to their release sites. Accurate regulation is conferred by proteins sensing Ca entering through voltage-gated Ca channels opened by an action potential. Presynaptic Ca concentration changes are dynamic functions in space and time, with wide fluctuations associated with different rates of neuronal activity. Thus, regulation of transmitter release includes reactions involving multiple Ca-dependent proteins, each operating over a specific time window. Classically, studies of presynaptic proteins function favored large invertebrate presynaptic terminals. I have established a useful mammalian synapse model based on sympathetic neurons in culture. This review summarizes the use of this model synapse to study the roles of presynaptic proteins in neuronal activity for the control of transmitter release efficacy and synaptic vesicle recycling.
Topics: Animals; Calcium; Calcium Channels; Humans; Neurons; Neurotransmitter Agents; Presynaptic Terminals; Proteins; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 29225307
DOI: 10.2183/pjab.93.050 -
Current Opinion in Neurobiology Apr 2017Effective adaptation of neural circuit function to a changing environment requires many forms of plasticity. Among these, structural plasticity is one of the most... (Review)
Review
Effective adaptation of neural circuit function to a changing environment requires many forms of plasticity. Among these, structural plasticity is one of the most durable, and is also an intrinsic part of the developmental logic for the formation and refinement of synaptic connectivity. Structural plasticity of presynaptic sites can involve the addition, remodeling, or removal of pre- and post-synaptic elements. However, this requires coordination of morphogenesis and assembly of the subcellular machinery for neurotransmitter release within the presynaptic neuron, as well as coordination of these events with the postsynaptic cell. While much progress has been made in revealing the cell biological mechanisms of postsynaptic structural plasticity, our understanding of presynaptic mechanisms is less complete.
Topics: Animals; Drosophila; Neuronal Plasticity; Presynaptic Terminals; Synaptic Transmission
PubMed: 28388491
DOI: 10.1016/j.conb.2017.03.003 -
The Journal of Physiology Dec 2017GABA receptors have been described in the axonal compartment of neurons; contrary to dendritic GABA receptors, axonal GABA receptors usually induce depolarizing...
KEY POINTS
GABA receptors have been described in the axonal compartment of neurons; contrary to dendritic GABA receptors, axonal GABA receptors usually induce depolarizing responses. In this study we describe the presence of functional axonal GABA receptors in cerebellar Purkinje cells by using a combination of direct patch-clamp recordings from the axon terminals and laser GABA photolysis. In Purkinje cells, axonal GABA receptors are depolarizing and induce an increase in neurotransmitter release that results in a change of short-term synaptic plasticity. These results contribute to our understanding of the cellular mechanisms of action of axonal GABA receptors and highlight the importance of the presynaptic compartment in neuronal computation.
ABSTRACT
In neurons of the adult brain, somatodendritic GABA receptors (GABA Rs) mediate fast synaptic inhibition and play a crucial role in synaptic integration. GABA Rs are not only present in the somatodendritic compartment, but also in the axonal compartment where they modulate action potential (AP) propagation and transmitter release. Although presynaptic GABA Rs have been reported in various brain regions, their mechanisms of action and physiological roles remain obscure, particularly at GABAergic boutons. Here, using a combination of direct whole-bouton or perforated patch-clamp recordings and local GABA photolysis in single axonal varicosities of cerebellar Purkinje cells, we investigate the subcellular localization and functional role of axonal GABA Rs both in primary cultures and acute slices. Our results indicate that presynaptic terminals of PCs carry GABA Rs that behave as auto-receptors; their activation leads to a depolarization of the terminal membrane after an AP due to the relatively high cytoplasmic Cl concentration in the axon, but they do not modulate the AP itself. Paired recordings from different terminals of the same axon show that the GABA R-mediated local depolarizations propagate substantially to neighbouring varicosities. Finally, the depolarization mediated by presynaptic GABA R activation augmented Ca influx and transmitter release, resulting in a marked effect on short-term plasticity. Altogether, our results reveal a mechanism by which presynaptic GABA Rs influence neuronal computation.
Topics: Action Potentials; Animals; Cells, Cultured; Exocytosis; Female; Male; Presynaptic Terminals; Purkinje Cells; Rats; Rats, Wistar; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 29072780
DOI: 10.1113/JP275369