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Hearing Research May 2018The ionotropic glutamate receptors (iGluRs) concertedly mediate neurotransmission to convey, process, and integrate acoustic information along the auditory pathway. In... (Review)
Review
The ionotropic glutamate receptors (iGluRs) concertedly mediate neurotransmission to convey, process, and integrate acoustic information along the auditory pathway. In order to ensure these challenging tasks, the iGluRs are variously expressed in auditory neurons in an age- and site-dependent manner. The subunit compositions of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs) are altered with development, underlying the acceleration in kinetics of excitatory postsynaptic responses. AMPAR desensitization partly affects short-term synaptic plasticity upon repetitive stimuli in subsets of auditory neurons at a given period of maturation. NMDAR activation is required for long-term synaptic plasticity in a cerebellum-like microcircuit within the first auditory brainstem nucleus. Along with their postsynaptic functions, AMPARs and NMDARs fulfill essential roles in presynaptic modulation of auditory neurotransmission. Despite the expression of the kainate and delta receptors, their functions remain unknown. Here this review aims to discuss the diverse distribution and functions of pre- and postsynaptic iGluRs in the peripheral and central auditory systems.
Topics: Animals; Auditory Pathways; Calcium Signaling; Glutamic Acid; Humans; Neuronal Plasticity; Receptors, Ionotropic Glutamate; Receptors, Presynaptic; Synaptic Membranes; Synaptic Transmission
PubMed: 29510886
DOI: 10.1016/j.heares.2018.02.007 -
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 -
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 -
Journal of Biochemistry Jun 2018Synaptic connections are essential for neural circuits in order to convey brain functions. The postsynaptic density (PSD) is a huge protein complex associated with... (Review)
Review
Synaptic connections are essential for neural circuits in order to convey brain functions. The postsynaptic density (PSD) is a huge protein complex associated with postsynaptic membranes of excitatory synapses. In mammals, the PSD is composed of more than 1,000 proteins including receptors, scaffold proteins, signalling enzymes and cytoskeletal proteins. PSD proteins are crucial for synaptic transmission and plasticity. Proteomic studies have revealed the composition of PSD proteins in various species, brain regions and specific physiological conditions. Abnormalities with PSD proteins are linked to various neuropsychiatric diseases including neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Here, we review different kinds of proteomic studies of the PSD and the involvement of PSD proteins in physiological and pathological conditions.
Topics: Animals; Humans; Nerve Tissue Proteins; Neurodevelopmental Disorders; Proteomics
PubMed: 29415158
DOI: 10.1093/jb/mvy022 -
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 -
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 -
Seminars in Cell & Developmental Biology Feb 2018The endosomal sorting complex required for transport (ESCRT) is made of subcomplexes (ESCRT 0-III), crucial to membrane remodelling at endosomes, nuclear envelope and... (Review)
Review
The endosomal sorting complex required for transport (ESCRT) is made of subcomplexes (ESCRT 0-III), crucial to membrane remodelling at endosomes, nuclear envelope and cell surface. ESCRT-III shapes membranes and in most cases cooperates with the ATPase VPS4 to mediate fission of membrane necks from the inside. The first ESCRT complexes mainly serve to catalyse the formation of ESCRT-III but can be bypassed by accessory proteins like the Alg-2 interacting protein-X (ALIX). In the nervous system, ALIX/ESCRT controls the survival of embryonic neural progenitors and later on the outgrowth and pruning of axons and dendrites, all necessary steps to establish a functional brain. In the adult brain, ESCRTs allow the endosomal turn over of synaptic vesicle proteins while stable ESCRT complexes might serve as scaffolds for the postsynaptic parts. The necessity of ESCRT for the harmonious function of the brain has its pathological counterpart, the mutations in CHMP2B of ESCRT-III giving rise to several neurodegenerative diseases.
Topics: Animals; Biological Transport; Endosomal Sorting Complexes Required for Transport; Humans; Nervous System
PubMed: 28811263
DOI: 10.1016/j.semcdb.2017.08.013 -
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