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Frontiers in Computational Neuroscience 2022The neuroscientific field benefits from the conjoint evolution of experimental and computational techniques, allowing for the reconstruction and simulation of complex... (Review)
Review
The neuroscientific field benefits from the conjoint evolution of experimental and computational techniques, allowing for the reconstruction and simulation of complex models of neurons and synapses. Chemical synapses are characterized by presynaptic vesicle cycling, neurotransmitter diffusion, and postsynaptic receptor activation, which eventually lead to postsynaptic currents and subsequent membrane potential changes. These mechanisms have been accurately modeled for different synapses and receptor types (AMPA, NMDA, and GABA) of the cerebellar cortical network, allowing simulation of their impact on computation. Of special relevance is short-term synaptic plasticity, which generates spatiotemporal filtering in local microcircuits and controls burst transmission and information flow through the network. Here, we present how data-driven computational models recapitulate the properties of neurotransmission at cerebellar synapses. The simulation of microcircuit models is starting to reveal how diverse synaptic mechanisms shape the spatiotemporal profiles of circuit activity and computation.
PubMed: 36387305
DOI: 10.3389/fncom.2022.1006989 -
International Journal of Molecular... Feb 2018The neuromuscular synapse is a relatively large synapse with hundreds of active zones in presynaptic motor nerve terminals and more than ten million acetylcholine... (Review)
Review
The neuromuscular synapse is a relatively large synapse with hundreds of active zones in presynaptic motor nerve terminals and more than ten million acetylcholine receptors (AChRs) in the postsynaptic membrane. The enrichment of proteins in presynaptic and postsynaptic membranes ensures a rapid, robust, and reliable synaptic transmission. Over fifty years ago, classic studies of the neuromuscular synapse led to a comprehensive understanding of how a synapse looks and works, but these landmark studies did not reveal the molecular mechanisms responsible for building and maintaining a synapse. During the past two-dozen years, the critical molecular players, responsible for assembling the specialized postsynaptic membrane and regulating nerve terminal differentiation, have begun to be identified and their mechanism of action better understood. Here, we describe and discuss five of these key molecular players, paying heed to their discovery as well as describing their currently understood mechanisms of action. In addition, we discuss the important gaps that remain to better understand how these proteins act to control synaptic differentiation and maintenance.
Topics: Animals; Biomarkers; Humans; LDL-Receptor Related Proteins; Muscle Proteins; Neuromuscular Junction; Receptors, Cholinergic; Synaptic Transmission
PubMed: 29415504
DOI: 10.3390/ijms19020490 -
The Journal of Physiology May 2016Activation of neurons not only changes their membrane potential and firing rate but as a secondary action reduces membrane resistance. This loss of resistance, or... (Review)
Review
Activation of neurons not only changes their membrane potential and firing rate but as a secondary action reduces membrane resistance. This loss of resistance, or increase of conductance, may be of central importance in non-invasive magnetic or electric stimulation of the human brain since electrical fields cause larger changes in transmembrane voltage in resting neurons with low membrane conductances than in active neurons with high conductance. This may explain why both the immediate effects and after-effects of brain stimulation are smaller or even reversed during voluntary activity compared with rest. Membrane conductance is also increased during shunting inhibition, which accompanies the classic GABAA IPSP. This short-circuits nearby EPSPs and is suggested here to contribute to the magnitude and time course of short-interval intracortical inhibition and intracortical facilitation.
Topics: Biophysical Phenomena; Excitatory Postsynaptic Potentials; Humans; Inhibitory Postsynaptic Potentials; Membrane Potentials; Neural Inhibition; Synapses
PubMed: 26940751
DOI: 10.1113/JP271452 -
Frontiers in Molecular Neuroscience 2021Regulated delivery of AMPA receptors (AMPARs) to the postsynaptic membrane is an essential step in synaptic strength modification, and in particular, long-term...
Regulated delivery of AMPA receptors (AMPARs) to the postsynaptic membrane is an essential step in synaptic strength modification, and in particular, long-term potentiation (LTP). While LTP has been extensively studied using electrophysiology and light microscopy, several questions regarding the molecular mechanisms of AMPAR delivery trafficking vesicles remain outstanding, including the gross molecular make up of AMPAR trafficking organelles and identification and location of calcium sensors required for SNARE complex-dependent membrane fusion of such trafficking vesicles with the plasma membrane. Here, we isolated AMPA-containing vesicles (ACVs) from whole mouse brains immunoisolation and characterized them using immunoelectron microscopy, immunoblotting, and liquid chromatography-tandem mass spectrometry (LC-MS/MS). We identified several proteins on ACVs that were previously found to play a role in AMPAR trafficking, including synaptobrevin-2, Rabs, the SM protein Munc18-1, the calcium-sensor synaptotagmin-1, as well as several new candidates, including synaptophysin and synaptogyrin on ACV membranes. Additionally, we identified two populations of ACVs based on size and molecular composition: small-diameter, synaptobrevin-2- and GluA1-containing ACVs, and larger transferrin- receptor-, GluA1-, GluA2-, and GluA3-containing ACVs. The small-diameter population of ACVs may represent a fusion-capable population of vesicles due to the presence of synaptobrevin-2. Because the fusion of ACVs may be a requisite of LTP, this population could represent trafficking vesicles related to LTP.
PubMed: 34720876
DOI: 10.3389/fnmol.2021.754631 -
Current Opinion in Structural Biology Feb 2019The postsynaptic density (PSD) is a protein-rich assembly below the postsynaptic membrane, formed of large scaffolding proteins. These proteins carry a combination of... (Review)
Review
The postsynaptic density (PSD) is a protein-rich assembly below the postsynaptic membrane, formed of large scaffolding proteins. These proteins carry a combination of protein interaction domains, which may interact with several alternative partners; the structure of the protein assembly can be regulated in an activity-dependent manner. A major scaffolding molecule in the PSD is Shank, a family of three main isoforms with highly similar domain structure. Proteins of the Shank family are targets of mutations in neurological disorders, such as autism and schizophrenia. All the predicted folded domains of Shank have now been crystallized. However, for an understanding of the structure and function of full-length Shank and its complexes in the supramolecular PSD assembly, novel complementary approaches and hybrid techniques must be employed.
Topics: Animals; Humans; Nerve Tissue Proteins; Nervous System Diseases; Post-Synaptic Density; Protein Domains
PubMed: 30849620
DOI: 10.1016/j.sbi.2019.01.007 -
Neural Plasticity 2018Aberrant regulation of oxytocin signaling is associated with the etiology of neurodevelopmental disorders. Synaptic dysfunctions in neurodevelopmental disorders are... (Review)
Review
Aberrant regulation of oxytocin signaling is associated with the etiology of neurodevelopmental disorders. Synaptic dysfunctions in neurodevelopmental disorders are becoming increasingly known, and their pathogenic mechanisms could be a target of potential therapeutic intervention. Therefore, it is important to pay attention to the role of oxytocin and its receptor in synapse structure, function, and neuron connectivity. An early alteration in oxytocin signaling may disturb neuronal maturation and may have short-term and long-term pathological consequences. At the molecular level, neurodevelopmental disorders include alterations in cytoskeletal rearrangement and neuritogenesis resulting in a diversity of synaptopathies. The presence of oxytocin receptors in the presynaptic and postsynaptic membranes and the direct effects of oxytocin on neuronal excitability by regulating the activity of ion channels in the cell membrane implicate that alterations in oxytocin signaling could be involved in synaptopathies. The ability of oxytocin to modulate neurogenesis, synaptic plasticity, and certain parameters of cytoskeletal arrangement is discussed in the present review.
Topics: Animals; Humans; Nerve Net; Neuronal Plasticity; Oxytocin; Receptors, Oxytocin; Signal Transduction; Synapses
PubMed: 30057594
DOI: 10.1155/2018/4864107 -
Communicative & Integrative Biology 2016The post-synaptic spines of neuronal dendrites are highly elaborate membrane protrusions. Their anatomy, stability and density are intimately linked to cognitive...
The post-synaptic spines of neuronal dendrites are highly elaborate membrane protrusions. Their anatomy, stability and density are intimately linked to cognitive performance. The morphological transitions of spines are powered by coordinated polymerization of actin filaments against the plasma membrane, but how the membrane-associated polymerization is spatially and temporally regulated has remained ill defined. Here, we discuss our recent findings showing that dendritic spines can be initiated by direct membrane bending by the I-BAR protein MIM/Mtss1. This lipid phosphatidylinositol (PI(4,5)P2) signaling-activated membrane bending coordinated spatial actin assembly and promoted spine formation. From recent advances, we formulate a general model to discuss how spatially concentrated protein-lipid microdomains formed by multivalent interactions between lipids and actin/membrane regulatory proteins might launch cell protrusions.
PubMed: 27489575
DOI: 10.1080/19420889.2015.1125053 -
Developmental Cell Oct 2020Formation of biomolecular condensates that are not enclosed by membranes via liquid-liquid phase separation (LLPS) is a general strategy that cells adopt to organize... (Review)
Review
Formation of biomolecular condensates that are not enclosed by membranes via liquid-liquid phase separation (LLPS) is a general strategy that cells adopt to organize membraneless subcellular compartments for diverse functions. Neurons are highly polarized with elaborate branching and functional compartmentalization of their neurites, thus, raising additional demand for the proper subcellular localization of both membraneless and membrane-based organelles. Recent studies have provided evidence that several protein assemblies involved in the establishment of neuronal stem cell (NSC) polarity and in the asymmetric division of NSCs form distinct molecular condensates via LLPS. In synapses of adult neurons, molecular apparatuses controlling presynaptic neurotransmitter release and postsynaptic signaling transmission are also likely formed via LLPS. These molecular condensates, though not enclosed by lipid bilayers, directly associate with plasma membranes or membrane-based organelles, indicating that direct communication between membraneless and membrane-based organelles is a common theme in neurons and other types of cells.
Topics: Animals; Cell Communication; Humans; Neurogenesis; Neurons; Organelles; Synapses; Synaptic Transmission
PubMed: 32726576
DOI: 10.1016/j.devcel.2020.06.012 -
Protein Science : a Publication of the... Nov 2021Chemical synaptic transmission represents the most sophisticated dynamic process and is highly regulated with optimized neurotransmitter balance. Imbalanced transmitters...
Chemical synaptic transmission represents the most sophisticated dynamic process and is highly regulated with optimized neurotransmitter balance. Imbalanced transmitters can lead to transmission impairments, for example, intracellular zinc accumulation is a hallmark of degenerating neurons. However, the underlying mechanisms remain elusive. Postsynaptic density protein-95 (PSD-95) is a primary postsynaptic membrane-associated protein and the major scaffolding component in the excitatory postsynaptic densities, which performs substantial functions in synaptic development and maturation. Its membrane association induced by palmitoylation contributes largely to its regulatory functions at postsynaptic sites. Unlike other structural domains in PSD-95, the N-terminal region (PSD-95NT) is flexible and interacts with various targets, which modulates its palmitoylation of two cysteines (C3/C5) and glutamate receptor distributions in postsynaptic densities. PSD-95NT contains a putative zinc-binding motif (C2H2) with undiscovered functions. This study is the first effort to investigate the interaction between Zn and PSD-95NT. The NMR titration of N-labeled PSD-95NT by ZnCl was performed and demonstrated Zn binds to PSD-95NT with a binding affinity (K ) in the micromolar range. The zinc binding was confirmed by fluorescence and mutagenesis assays, indicating two cysteines and two histidines (H24, H28) are critical residues for the binding. These results suggested the concentration-dependent zinc binding is likely to influence PSD-95 palmitoylation since the binding site overlaps the palmitoylation sites, which was verified by the mimic PSD-95 palmitoyl modification and intact cell palmitoylation assays. This study reveals zinc as a novel modulator for PSD-95 postsynaptic membrane association by chelating its N-terminal region, indicative of its importance in postsynaptic signaling.
Topics: Amino Acid Motifs; Chelating Agents; Disks Large Homolog 4 Protein; HEK293 Cells; Humans; Lipoylation; Protein Domains; Zinc
PubMed: 34538002
DOI: 10.1002/pro.4187 -
Frontiers in Molecular Neuroscience 2015Changes in synaptic strength underlie the basis of learning and memory and are controlled, in part, by the insertion or removal of AMPA-type glutamate receptors at the... (Review)
Review
Changes in synaptic strength underlie the basis of learning and memory and are controlled, in part, by the insertion or removal of AMPA-type glutamate receptors at the postsynaptic membrane of excitatory synapses. Once internalized, these receptors may be recycled back to the plasma membrane by subunit-specific interactions with other proteins or by post-translational modifications such as phosphorylation. Alternatively, these receptors may be targeted for destruction by multiple degradation pathways in the cell. Ubiquitination, another post-translational modification, has recently emerged as a key signal that regulates the recycling and trafficking of glutamate receptors. In this review, we will discuss recent findings on the role of ubiquitination in the trafficking and turnover of ionotropic glutamate receptors and plasticity of excitatory synapses.
PubMed: 26528125
DOI: 10.3389/fnmol.2015.00060