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Nature Neuroscience Jun 2023Endocannabinoids are among the most powerful modulators of synaptic transmission throughout the nervous system, and yet little is understood about the release of...
Endocannabinoids are among the most powerful modulators of synaptic transmission throughout the nervous system, and yet little is understood about the release of endocannabinoids from postsynaptic compartments. Here we report an unexpected finding that endocannabinoid release requires synucleins, key contributors to Parkinson's disease. We show that endocannabinoids are released postsynaptically by a synuclein-dependent and SNARE-dependent mechanism. Specifically, we found that synuclein deletion blocks endocannabinoid-dependent synaptic plasticity; this block is reversed by postsynaptic expression of wild-type but not of mutant α-synuclein. Whole-cell recordings and direct optical monitoring of endocannabinoid signaling suggest that the synuclein deletion specifically blocks endocannabinoid release. Given the presynaptic role of synucleins in regulating vesicle lifecycle, we hypothesize that endocannabinoids are released via a membrane interaction mechanism. Consistent with this hypothesis, postsynaptic expression of tetanus toxin light chain, which cleaves synaptobrevin SNAREs, also blocks endocannabinoid-dependent signaling. The unexpected finding that endocannabinoids are released via a synuclein-dependent mechanism is consistent with a general function of synucleins in membrane trafficking and adds a piece to the longstanding puzzle of how neurons release endocannabinoids to induce synaptic plasticity.
Topics: Endocannabinoids; Signal Transduction; Synaptic Transmission; Neurons; Cell Communication
PubMed: 37248337
DOI: 10.1038/s41593-023-01345-0 -
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 -
Traffic (Copenhagen, Denmark) Sep 2007Neurons are communication specialists that convert electrical into chemical signals at specialized cell-cell junctions termed synapses. Arrival of an action potential... (Review)
Review
Neurons are communication specialists that convert electrical into chemical signals at specialized cell-cell junctions termed synapses. Arrival of an action potential triggers calcium-regulated exocytosis of neurotransmitter (NT) from small synaptic vesicles (SVs), which then diffuses across the synaptic cleft and binds to postsynaptic receptors to elicit specific changes within the postsynaptic cell. Endocytosis of pre- and postsynaptic membrane proteins including SV components and postsynaptic NT receptors is essential for the proper functioning of the synapse. During the past several years, we have witnessed enormous progress in our understanding of the mechanics of clathrin-mediated endocytosis (CME) and its role in regulating exo-endocytic vesicle cycling at synapses. Here we summarize the molecular machinery used for recognition of synaptic membrane protein cargo and its clathrin-dependent internalization, and describe the inventory of tools that can be used to monitor vesicle cycling at synapses or to inhibit CME in a stage-specific manner.
Topics: Adaptor Proteins, Vesicular Transport; Animals; Clathrin-Coated Vesicles; Endocytosis; Humans; Models, Biological; Receptors, Neurotransmitter; Synapses; Synaptic Membranes; Synaptic Vesicles
PubMed: 17547698
DOI: 10.1111/j.1600-0854.2007.00595.x -
Advances in Biological Regulation Jan 2020Diacylglycerol kinases (DGKs) contribute to an important part of intracellular signaling because, in addition to reducing diacylglycerol levels, they generate... (Review)
Review
Diacylglycerol kinases (DGKs) contribute to an important part of intracellular signaling because, in addition to reducing diacylglycerol levels, they generate phosphatidic acid (PtdOH) Recent research has led to the discovery of ten mammalian DGK isoforms, all of which are found in the mammalian brain. Many of these isoforms have studied functions within the brain, while others lack such understanding in regards to neuronal roles, regulation, and structural dynamics. However, while previously a neuronal function for DGKθ was unknown, it was recently found that DGKθ is required for the regulation of synaptic vesicle endocytosis and work is currently being conducted to elucidate the mechanism behind this regulation. Here we will review some of the roles of all mammalian DGKs and hypothesize additional roles. We will address the topic of redundancy among the ten DGK isoforms and discuss the possibility that DGKθ, among other DGKs, may have unstudied postsynaptic functions. We also hypothesize that in addition to DGKθ's presynaptic endocytic role, DGKθ might also regulate the endocytosis of AMPA receptors and other postsynaptic membrane proteins.
Topics: Animals; Diacylglycerol Kinase; Endocytosis; Humans; Isoenzymes; Mice; Neurons; Phosphatidic Acids; Receptors, AMPA; Synaptic Membranes; Synaptic Vesicles
PubMed: 31836314
DOI: 10.1016/j.jbior.2019.100688 -
Brain Research Bulletin Mar 2017In the adult mammalian brain, GABAergic neurotransmission provides the majority of synaptic inhibition that balances glutamatergic excitatory drive and thereby controls... (Review)
Review
In the adult mammalian brain, GABAergic neurotransmission provides the majority of synaptic inhibition that balances glutamatergic excitatory drive and thereby controls neuronal output. It is generally accepted that synaptogenesis is initiated through highly specific protein-protein interactions mediated by membrane proteins expressed in developing presynaptic terminals and postsynaptic membranes. Accumulating studies have uncovered a number of membrane proteins that regulate different aspects of GABAergic synapse development. In this review, we summarize recent advances in understanding of GABAergic synapse development with a focus on postsynaptic membrane molecules, including receptors, synaptogenic cell adhesion molecules and immunoglobulin superfamily proteins.
Topics: Animals; Brain; GABAergic Neurons; Membrane Proteins; Nerve Tissue Proteins; Synapses
PubMed: 27453545
DOI: 10.1016/j.brainresbull.2016.07.004 -
Nature Reviews. Neuroscience Mar 2014The neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligand-gated chloride channels--namely, type A GABA (GABA(A)) and glycine... (Review)
Review
The neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligand-gated chloride channels--namely, type A GABA (GABA(A)) and glycine receptors. Both types of receptors are anchored postsynaptically by gephyrin, which self-assembles into a scaffold and interacts with the cytoskeleton. Current research indicates that postsynaptic gephyrin clusters are dynamic assemblies that are held together and regulated by multiple protein-protein interactions. Moreover, post-translational modifications of gephyrin regulate the formation and plasticity of GABAergic synapses by altering the clustering properties of postsynaptic scaffolds and thereby the availability and function of receptors and other signalling molecules. Here, we discuss the formation and regulation of the gephyrin scaffold, its role in GABAergic and glycinergic synaptic function and the implications for the pathophysiology of brain disorders caused by abnormal inhibitory neurotransmission.
Topics: Animals; Carrier Proteins; Hippocampus; Membrane Proteins; Neurons; Receptors, GABA-A; Receptors, Glycine; Synapses
PubMed: 24552784
DOI: 10.1038/nrn3670 -
PloS One 2018Densin is a scaffold protein known to associate with key elements of neuronal signaling. The present study examines the distribution of densin at the ultrastructural...
Densin is a scaffold protein known to associate with key elements of neuronal signaling. The present study examines the distribution of densin at the ultrastructural level in order to reveal potential sites that can support specific interactions of densin. Immunogold electron microscopy on hippocampal cultures shows intense labeling for densin at postsynaptic densities (PSDs), but also some labeling at extrasynaptic plasma membranes of soma and dendrites and endoplasmic reticulum. At the PSD, the median distance of label from the postsynaptic membrane was ~27 nm, with the majority of label (90%) confined within 40 nm from the postsynaptic membrane, indicating predominant localization of densin at the PSD core. Depolarization (90 mM K+ for 2 min) promoted a slight shift of densin label within the PSD complex resulting in 77% of label remaining within 40 nm from the postsynaptic membrane. Densin molecules firmly embedded within the PSD may target a minor pool of CaMKII to substrates at the PSD core.
Topics: Animals; Brain; Brain Mapping; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Membrane; Cells, Cultured; Dendrites; Endoplasmic Reticulum; Female; Hippocampus; Immunohistochemistry; Male; Nerve Tissue Proteins; Neurons; Post-Synaptic Density; Protein Binding; Rats; Rats, Sprague-Dawley; Sialoglycoproteins; Subcellular Fractions
PubMed: 30325965
DOI: 10.1371/journal.pone.0205859 -
Journal of Neurochemistry Oct 2011J. Neurochem. (2011) 119, 64-77.
UNLABELLED
J. Neurochem. (2011) 119, 64-77.
ABSTRACT
Postsynaptic membrane rafts are believed to play important roles in synaptic signaling, plasticity, and maintenance. However, their molecular identities remain elusive. Further, how they interact with the well-established signaling specialization, the postsynaptic density (PSD), is poorly understood. We previously detected a number of conventional PSD proteins in detergent-resistant membranes (DRMs). Here, we have performed liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) analyses on postsynaptic membrane rafts and PSDs. Our comparative analysis identified an extensive overlap of protein components in the two structures. This overlapping could be explained, at least partly, by a physical association of the two structures. Meanwhile, a significant number of proteins displayed biased distributions to either rafts or PSDs, suggesting distinct roles for the two postsynaptic specializations. Using biochemical and electron microscopic methods, we directly detected membrane raft-PSD complexes. In vitro reconstitution experiments indicated that the formation of raft-PSD complexes was not because of the artificial reconstruction of once-solubilized membrane components and PSD structures, supporting that these complexes occurred in vivo. Taking together, our results provide evidence that postsynaptic membrane rafts and PSDs may be physically associated. Such association could be important in postsynaptic signal integration, synaptic function, and maintenance.
Topics: Animals; Centrifugation, Density Gradient; Cholesterol; Chromatography, High Pressure Liquid; Detergents; Electrophoresis, Polyacrylamide Gel; G(M1) Ganglioside; Male; Mass Spectrometry; Membrane Microdomains; Microscopy, Electron; Nerve Tissue Proteins; Octoxynol; Proteomics; Rats; Rats, Wistar; Synapses
PubMed: 21797867
DOI: 10.1111/j.1471-4159.2011.07404.x -
Molecular Neurobiology Feb 2012Organization of presynaptic active zones is essential for development, plasticity, and pathology of the nervous system. Recent studies indicate a trans-synaptic... (Review)
Review
Organization of presynaptic active zones is essential for development, plasticity, and pathology of the nervous system. Recent studies indicate a trans-synaptic molecular mechanism that organizes the active zones by connecting the pre- and the postsynaptic specialization. The presynaptic component of this trans-synaptic mechanism is comprised of cytosolic active zone proteins bound to the cytosolic domains of voltage-dependent calcium channels (P/Q-, N-, and L-type) on the presynaptic membrane. The postsynaptic component of this mechanism is the synapse organizer (laminin β2) that is expressed by the postsynaptic cell and accumulates specifically on top of the postsynaptic specialization. The pre- and the postsynaptic components interact directly between the extracellular domains of calcium channels and laminin β2 to anchor the presynaptic protein complex in front of the postsynaptic specialization. Hence, the presynaptic calcium channel functions as a scaffolding protein for active zone organization and as an ion-conducting channel for synaptic transmission. In contrast to the requirement of calcium influx for synaptic transmission, the formation of the active zone does not require the calcium influx through the calcium channels. Importantly, the active zones of adult synapses are not stable structures and require maintenance for their integrity. Furthermore, aging or diseases of the central and peripheral nervous system impair the active zones. This review will focus on the molecular mechanisms that organize the presynaptic active zones and summarize recent findings at the neuromuscular junctions and other synapses.
Topics: Animals; Calcium Channels; Humans; Neuromuscular Junction; Post-Synaptic Density; Presynaptic Terminals; Synaptic Membranes; Synaptic Transmission; Vertebrates
PubMed: 22135013
DOI: 10.1007/s12035-011-8216-y -
The Journal of Cell Biology Apr 2014Insights into mechanisms coordinating membrane remodeling, local actin nucleation, and postsynaptic scaffolding during postsynapse formation are important for...
Insights into mechanisms coordinating membrane remodeling, local actin nucleation, and postsynaptic scaffolding during postsynapse formation are important for understanding vertebrate brain function. Gene knockout and RNAi in individual neurons reveal that the F-BAR protein syndapin I is a crucial postsynaptic coordinator in formation of excitatory synapses. Syndapin I deficiency caused significant reductions of synapse and dendritic spine densities. These syndapin I functions reflected direct, SH3 domain-mediated associations and functional interactions with ProSAP1/Shank2. They furthermore required F-BAR domain-mediated membrane binding. Ultra-high-resolution imaging of specifically membrane-associated, endogenous syndapin I at membranes of freeze-fractured neurons revealed that membrane-bound syndapin I preferentially occurred in spines and formed clusters at distinct postsynaptic membrane subareas. Postsynaptic syndapin I deficiency led to reduced frequencies of miniature excitatory postsynaptic currents, i.e., to defects in synaptic transmission phenocopying ProSAP1/Shank2 knockout, and impairments in proper synaptic ProSAP1/Shank2 distribution. Syndapin I-enriched membrane nanodomains thus seem to be important spatial cues and organizing platforms, shaping dendritic membrane areas into synaptic compartments.
Topics: Animals; Dendrites; HEK293 Cells; Humans; Membrane Microdomains; Mice; Mice, Knockout; Nerve Tissue Proteins; Protein Structure, Tertiary; Synapses; Synaptic Potentials; Syndecan-1
PubMed: 24751538
DOI: 10.1083/jcb.201307088