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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 -
Current Opinion in Neurobiology Jun 2012The unique ability of chemical synapses to transmit information relies on the structural organization of presynaptic terminals. Empowered by forward genetics, research... (Review)
Review
The unique ability of chemical synapses to transmit information relies on the structural organization of presynaptic terminals. Empowered by forward genetics, research using Caenorhabditis elegans has continued to make pivotal contributions to discover conserved regulators and pathways for presynaptic development. Recent advances in microscopy have begun to pave the path for linking molecular dynamics with subsynaptic structures. Studies using diverse reporters for synapses further broaden the landscape of regulatory mechanisms underlying presynaptic differentiation. The identification of novel regulators at transcriptional and post-transcriptional levels raises new questions for understanding synapse formation at the genomic scale.
Topics: Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Presynaptic Terminals; Synapses; Ultrasonography
PubMed: 22036768
DOI: 10.1016/j.conb.2011.10.002 -
Cellular and Molecular Life Sciences :... Jan 2001Synapses are principal sites for communication between neurons via chemical messengers called neurotransmitters. Neurotransmitters are released from presynaptic nerve... (Review)
Review
Synapses are principal sites for communication between neurons via chemical messengers called neurotransmitters. Neurotransmitters are released from presynaptic nerve terminals at the active zone, a restricted area of the cell membrane situated exactly opposite to the postsynaptic neurotransmitter reception apparatus. At the active zone neurotransmitter-containing synaptic vesicles (SVs) dock, fuse, release their content and are recycled in a strictly regulated manner. The cytoskeletal matrix at the active zone (CAZ) is thought to play an essential role in the organization of this SV cycle. Several multi-domain cytoskeleton-associated proteins, including RIM, Bassoon, Piccolo/Aczonin and Munc-13, have been identified, which are specifically localized at the active zone and thus are putative molecular components of the CAZ. This review will summarize our present knowledge about the structure and function of these CAZ-specific proteins. Moreover, we will review our present view of how the exocytotic and endocytic machineries at the site of neurotransmitter release are linked to and organized by the presynaptic cytoskeleton. Finally, we will summarize recent progress that has been made in understanding how active zones are assembled during nervous system development.
Topics: Animals; Brain; Cell Membrane; Cytoskeleton; Endocytosis; Exocytosis; Mitochondria; Nerve Tissue Proteins; Neurotransmitter Agents; Presynaptic Terminals; Synaptic Vesicles
PubMed: 11229820
DOI: 10.1007/PL00000781 -
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 -
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 -
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 -
Neural Plasticity 2012In mammalian brain, the cellular and molecular events occurring in both synapse formation and plasticity are difficult to study due to the large number of factors... (Review)
Review
In mammalian brain, the cellular and molecular events occurring in both synapse formation and plasticity are difficult to study due to the large number of factors involved in these processes and because the contribution of each component is not well defined. Invertebrates, such as Drosophila, Aplysia, Helix, Lymnaea, and Helisoma, have proven to be useful models for studying synaptic assembly and elementary forms of learning. Simple nervous system, cellular accessibility, and genetic simplicity are some examples of the invertebrate advantages that allowed to improve our knowledge about evolutionary neuronal conserved mechanisms. In this paper, we present an overview of progresses that elucidates cellular and molecular mechanisms underlying synaptogenesis and synapse plasticity in invertebrate varicosities and their validation in vertebrates. In particular, the role of invertebrate synapsin in the formation of presynaptic terminals and the cell-to-cell interactions that induce specific structural and functional changes in their respective targets will be analyzed.
Topics: Animals; Cell Communication; Invertebrates; Learning; Neurites; Neuronal Plasticity; Presynaptic Terminals; Synapses; Synapsins
PubMed: 22655209
DOI: 10.1155/2012/670821 -
Biological Chemistry Sep 2023The distance between Ca2.1 voltage-gated Ca channels and the Ca sensor responsible for vesicle release at presynaptic terminals is critical for determining synaptic...
The distance between Ca2.1 voltage-gated Ca channels and the Ca sensor responsible for vesicle release at presynaptic terminals is critical for determining synaptic strength. Yet, the molecular mechanisms responsible for a loose coupling configuration of Ca2.1 in certain synapses or developmental periods and a tight one in others remain unknown. Here, we examine the nanoscale organization of two Ca2.1 splice isoforms (Ca2.1[EFa] and Ca2.1[EFb]) at presynaptic terminals by superresolution structured illumination microscopy. We find that Ca2.1[EFa] is more tightly co-localized with presynaptic markers than Ca2.1[EFb], suggesting that alternative splicing plays a crucial role in the synaptic organization of Ca2.1 channels.
Topics: Synaptic Vesicles; Presynaptic Terminals; Protein Isoforms; Synapses
PubMed: 37658578
DOI: 10.1515/hsz-2023-0235 -
Philosophical Transactions of the Royal... Jan 2014Long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus has been investigated in great detail over the past 40 years. Where and how LTP is... (Review)
Review
Long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus has been investigated in great detail over the past 40 years. Where and how LTP is actually expressed, however, remain controversial issues. Considerable evidence has been offered to support both pre- and postsynaptic contributions to LTP expression. Though it is widely held that postsynaptic expression mechanisms are the primary contributors to LTP expression, evidence for that conclusion is amenable to alternative explanations. Here, we briefly review some key contributions to the 'locus' debate and describe data that support a dominant role for presynaptic mechanisms. Recognition of the state-dependency of expression mechanisms, and consideration of the consequences of the spatial relationship between postsynaptic glutamate receptors and presynaptic vesicular release sites, lead to a model that may reconcile views from both sides of the synapse.
Topics: Excitatory Postsynaptic Potentials; Glutamic Acid; Hippocampus; Humans; Long-Term Potentiation; Models, Neurological; Neurotransmitter Agents; Presynaptic Terminals
PubMed: 24298138
DOI: 10.1098/rstb.2013.0135