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Cerebral Cortex (New York, N.Y. : 1991) Sep 2018A delicate interneuronal communication between pre- and postsynaptic membranes is critical for synaptic plasticity and the formation of memory. Evidence shows that...
A delicate interneuronal communication between pre- and postsynaptic membranes is critical for synaptic plasticity and the formation of memory. Evidence shows that membrane/lipid rafts (MLRs), plasma membrane microdomains enriched in cholesterol and sphingolipids, organize presynaptic proteins and postsynaptic receptors necessary for synaptic formation and signaling. MLRs establish a cell polarity that facilitates transduction of extracellular cues to the intracellular environment. Here we show that neuron-targeted overexpression of an MLR protein, caveolin-1 (SynCav1), in the adult mouse hippocampus increased the number of presynaptic vesicles per bouton, total excitatory type I glutamatergic synapses, number of same-dendrite multiple-synapse boutons, increased myelination, increased long-term potentiation, and increased MLR-localized N-methyl-d-aspartate receptor subunits (GluN1, GluN2A, and GluN2B). Immunogold electron microscopy revealed that Cav-1 localizes to both the pre- and postsynaptic membrane regions as well as in the synaptic cleft. These findings, which are consistent with a significant increase in ultrastructural and functional synaptic plasticity, provide a fundamental framework that underlies previously demonstrated improvements in learning and memory in adult and aged mice by SynCav1. Such observations suggest that Cav-1 and MLRs alter basic aspects of synapse biology that could serve as potential therapeutic targets to promote neuroplasticity and combat neurodegeneration in a number of neurological disorders.
Topics: Animals; Caveolin 1; Hippocampus; Mice; Mice, Inbred C57BL; Neuronal Plasticity; Neurons
PubMed: 28981594
DOI: 10.1093/cercor/bhx196 -
Journal of Neuroscience Research Feb 2024Synapses serve as the points of communication between neurons, consisting primarily of three components: the presynaptic membrane, synaptic cleft, and postsynaptic... (Review)
Review
Synapses serve as the points of communication between neurons, consisting primarily of three components: the presynaptic membrane, synaptic cleft, and postsynaptic membrane. They transmit signals through the release and reception of neurotransmitters. Synaptic plasticity, the ability of synapses to undergo structural and functional changes, is influenced by proteins such as growth-associated proteins, synaptic vesicle proteins, postsynaptic density proteins, and neurotrophic growth factors. Furthermore, maintaining synaptic plasticity consumes more than half of the brain's energy, with a significant portion of this energy originating from ATP generated through mitochondrial energy metabolism. Consequently, the quantity, distribution, transport, and function of mitochondria impact the stability of brain energy metabolism, thereby participating in the regulation of fundamental processes in synaptic plasticity, including neuronal differentiation, neurite outgrowth, synapse formation, and neurotransmitter release. This article provides a comprehensive overview of the proteins associated with presynaptic plasticity, postsynaptic plasticity, and common factors between the two, as well as the relationship between mitochondrial energy metabolism and synaptic plasticity.
Topics: Synapses; Synaptic Transmission; Mitochondria; Neuronal Plasticity; Autophagy
PubMed: 38400573
DOI: 10.1002/jnr.25309 -
Journal of Visualized Experiments : JoVE Sep 2022Synaptic terminals are the primary sites of neuronal communication. Synaptic dysfunction is a hallmark of many neuropsychiatric and neurological disorders. The...
Synaptic terminals are the primary sites of neuronal communication. Synaptic dysfunction is a hallmark of many neuropsychiatric and neurological disorders. The characterization of synaptic sub-compartments by biochemical isolation is, therefore, a powerful method to elucidate the molecular bases of synaptic processes, both in health and disease. This protocol describes the isolation of synaptic terminals and synaptic sub-compartments from mouse brains by subcellular fractionation. First, sealed synaptic terminal structures, known as synaptosomes, are isolated following brain tissue homogenization. Synaptosomes are neuronal pre- and post-synaptic compartments with pinched-off and sealed membranes. These structures retain a metabolically active state and are valuable for studying synaptic structure and function. The synaptosomes are then subjected to hypotonic lysis and ultracentrifugation to obtain synaptic sub-compartments enriched for synaptic vesicles, synaptic cytosol, and synaptic plasma membrane. Fraction purity is confirmed by electron microscopy and biochemical enrichment analysis for proteins specific to sub-synaptic compartments. The presented method is a straightforward and valuable tool for studying the structural and functional characteristics of the synapse and the molecular etiology of various brain disorders.
Topics: Animals; Brain; Cell Fractionation; Mice; Subcellular Fractions; Synaptic Membranes; Synaptic Vesicles; Synaptosomes
PubMed: 36190269
DOI: 10.3791/64574 -
BMC Bioinformatics Sep 2020The key role in the dynamic regulation of synaptic protein turnover belongs to the Fragile X Mental Retardation Protein, which regulates the efficiency of dendritic mRNA...
BACKGROUND
The key role in the dynamic regulation of synaptic protein turnover belongs to the Fragile X Mental Retardation Protein, which regulates the efficiency of dendritic mRNA translation in response to stimulation of metabotropic glutamate receptors at excitatory synapses of the hippocampal pyramidal cells. Its activity is regulated via positive and negative regulatory loops that function in different time ranges, which is an absolute factor for the formation of chaotic regimes that lead to disrupted proteome stability. The indicated condition may cause a number of neuropsychiatric diseases, including autism and epilepsy. The present study is devoted to a theoretical analysis of the local translation system dynamic properties and identification of parameters affecting the chaotic potential of the system.
RESULTS
A mathematical model that describes the maintenance of a specific pool of active receptors on the postsynaptic membrane via two mechanisms - de novo synthesis of receptor proteins and restoration of protein function during the recycling process - has been developed. Analysis of the model revealed that an increase in the values of the parameters describing the impact of protein recycling on the maintenance of a pool of active receptors in the membrane, duration of the signal transduction via the mammalian target of rapamycin pathway, influence of receptors on the translation activation, as well as reduction of the rate of synthesis and integration of de novo synthesized proteins into the postsynaptic membrane - contribute to the reduced complexity of the local translation system dynamic state. Formation of these patterns significantly depends on the complexity and non-linearity of the mechanisms of exposure of de novo synthesized receptors to the postsynaptic membrane, the correct evaluation of which is currently problematic.
CONCLUSIONS
The model predicts that an increase of "receptor recycling" and reduction of the rate of synthesis and integration of de novo synthesized proteins into the postsynaptic membrane contribute to the reduced complexity of the local translation system dynamic state. Herewith, stable stationary states occur much less frequently than cyclic states. It is possible that cyclical nature of functioning of the local translation system is its "normal" dynamic state.
Topics: Fragile X Mental Retardation Protein; Gene Expression Regulation; Hippocampus; Humans; Models, Biological; Protein Biosynthesis; Receptors, Metabotropic Glutamate; Signal Transduction; Synapses
PubMed: 32921299
DOI: 10.1186/s12859-020-03597-0 -
IScience Aug 2020Cell membranes often contain domains with important physiological functions. A typical example are neuronal synapses, whose capacity to capture receptors for...
Cell membranes often contain domains with important physiological functions. A typical example are neuronal synapses, whose capacity to capture receptors for neurotransmitters is central to neuronal functions. Receptors diffuse in the membrane until they are stabilized by interactions with stable elements, the scaffold. Single particle tracking experiments demonstrated that these interactions are rather weak and that lateral diffusion is strongly impaired in the post-synaptic membrane due to molecular crowding. We investigated how the distribution of scaffolding molecules and molecular crowding affect the capture of receptors. In particle-based Monte Carlo simulations, based on experimental data of molecular diffusion and organization, crowding enhanced the receptor-scaffold interaction but reduced the capture of new molecules. The distribution of scaffolding sites in several clusters reduced crowding and fostered the exchange of molecules accelerating synaptic plasticity. Synapses could switch between two regimes, becoming more stable or more plastic depending on the internal distribution of molecules.
PubMed: 32739837
DOI: 10.1016/j.isci.2020.101382 -
Frontiers in Cellular Neuroscience 2022NMDA receptors (NMDARs) are crucial for glutamatergic synaptic signaling in the mammalian central nervous system. When activated by glutamate and glycine/D-serine, the...
NMDA receptors (NMDARs) are crucial for glutamatergic synaptic signaling in the mammalian central nervous system. When activated by glutamate and glycine/D-serine, the NMDAR ion channel can open, but current flux is further regulated by voltage-dependent block conferred by extracellular Mg ions. The unique biophysical property of ligand- and voltage-dependence positions NMDARs as synaptic coincidence detectors, controlling a major source of synaptic Ca influx. We measured synaptic currents in layer 2/3 neurons after stimulation in layer 4 of somatosensory cortex and found measurable NMDAR currents at all voltages tested. This NMDAR current did not require concurrent AMPAR depolarization. In physiological ionic conditions, the NMDAR current response at negative potentials was enhanced relative to ionic conditions typically used in slice experiments. NMDAR activity was also seen in synaptic recordings from hippocampal CA1 neurons, indicating a general property of NMDAR signaling. Using a fluorescent Ca indicator, we measured responses to stimulation in layer 4 at individual synaptic sites, and Ca influx could be detected even with AMPARs blocked. In current clamp recordings, we found that resting membrane potential was hyperpolarized by ∼7 mV and AP firing threshold depolarized by ∼4 mV in traditional compared to physiological ionic concentrations, and that NMDARs contribute to EPSPs at resting membrane potentials. These measurements demonstrate that, even in the presence of extracellular Mg and absence of postsynaptic depolarization, NMDARs contribute to synaptic currents and Ca influx.
PubMed: 35928574
DOI: 10.3389/fncel.2022.916626 -
Current Opinion in Neurobiology Aug 2019The postsynaptic density (PSD) is an electron dense, semi-membrane bound compartment that lies beneath postsynaptic membranes. This region is densely packed with... (Review)
Review
The postsynaptic density (PSD) is an electron dense, semi-membrane bound compartment that lies beneath postsynaptic membranes. This region is densely packed with thousands of proteins that are involved in extensive interactions. During synaptic plasticity, the PSD undergoes changes in size and composition along with changes in synaptic strength that lead to long term potentiation (LTP) or depression (LTD). It is therefore essential to understand the organization principles underlying PSD assembly and rearrangement. Here, we review exciting new findings from recent in vitro reconstitution studies and propose a hypothesis that liquid-liquid phase separation mediates PSD formation and regulation. We also discuss how the properties of PSD formed via phase separation might contribute to the biological functions observed from decades of researches. Finally, we highlight unanswered questions regarding PSD organization and how in vitro reconstitution systems may help to answer these questions in the coming years.
Topics: Hippocampus; Long-Term Potentiation; Neuronal Plasticity; Post-Synaptic Density; Signal Transduction; Synapses
PubMed: 30599311
DOI: 10.1016/j.conb.2018.12.001 -
Molecular Biology of the Cell Sep 2015Membranes form elaborate structures that are highly tailored to their specialized cellular functions, yet the mechanisms by which these structures are shaped remain...
Membranes form elaborate structures that are highly tailored to their specialized cellular functions, yet the mechanisms by which these structures are shaped remain poorly understood. Here, we show that the conserved membrane-remodeling C-terminal Eps15 Homology Domain (EHD) protein Past1 is required for the normal assembly of the subsynaptic muscle membrane reticulum (SSR) at the Drosophila melanogaster larval neuromuscular junction (NMJ). past1 mutants exhibit altered NMJ morphology, decreased synaptic transmission, reduced glutamate receptor levels, and a deficit in synaptic homeostasis. The membrane-remodeling proteins Amphiphysin and Syndapin colocalize with Past1 in distinct SSR subdomains and collapse into Amphiphysin-dependent membrane nodules in the SSR of past1 mutants. Our results suggest a mechanism by which the coordinated actions of multiple lipid-binding proteins lead to the elaboration of increasing layers of the SSR and uncover new roles for an EHD protein at synapses.
Topics: Adaptor Proteins, Signal Transducing; Animals; Carrier Proteins; Drosophila Proteins; Drosophila melanogaster; Larva; Nerve Tissue Proteins; Neuromuscular Junction; Presynaptic Terminals; Receptors, Glutamate; Synaptic Membranes
PubMed: 26202464
DOI: 10.1091/mbc.E15-02-0093 -
Journal of Neurophysiology Aug 2019How neurons filter and integrate their complex patterns of synaptic inputs is central to their role in neural information processing. Synaptic filtering and integration...
How neurons filter and integrate their complex patterns of synaptic inputs is central to their role in neural information processing. Synaptic filtering and integration are shaped by the frequency-dependent neuronal membrane impedance. Using single and dual dendritic recordings in vivo, pharmacology, and computational modeling, we characterized the membrane impedance of a collision detection neuron in the grasshopper . This neuron, the lobula giant movement detector (LGMD), exhibits consistent impedance properties across frequencies and membrane potentials. Two common active conductances and , mediated respectively by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and by muscarine-sensitive M-type K channels, promote broadband integration with high temporal precision over the LGMD's natural range of membrane potentials and synaptic input frequencies. Additionally, we found that a model based on the LGMD's branching morphology increased the gain and decreased the delay associated with the mapping of synaptic input currents to membrane potential. More generally, this was true for a wide range of model neuron morphologies, including those of neocortical pyramidal neurons and cerebellar Purkinje cells. These findings show the unexpected role played by two widespread active conductances and by dendritic morphology in shaping synaptic integration. Neuronal filtering and integration of synaptic input patterns depend on the electrochemical properties of dendrites. We used an identified collision detection neuron in grasshoppers to examine how its morphology and two conductances affect its membrane impedance in relation to the computations it performs. The neuronal properties examined are ubiquitous and therefore promote a general understanding of neuronal computations, including those in the human brain.
Topics: Animals; Dendrites; Electric Impedance; Excitatory Postsynaptic Potentials; Female; Grasshoppers; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Models, Biological; Motion Perception; Neurons; Potassium Channel Blockers
PubMed: 31268830
DOI: 10.1152/jn.00048.2019 -
Faculty Reviews 2022Synapses are specialized cellular junctions essential for communication between neurons. Synapse loss occurs in many neurodegenerative diseases. Harnessing our molecular...
Synapses are specialized cellular junctions essential for communication between neurons. Synapse loss occurs in many neurodegenerative diseases. Harnessing our molecular knowledge of the development and maintenance of synapses, Suzuki . present the first comprehensive attempt to use a synthetic protein to bridge the pre- and postsynaptic membranes. They show that this powerful approach can stimulate the formation of pre- and postsynaptic specializations , rescue synaptic deficits of mutant mice , and ameliorate synapse loss and behavioral abnormalities in both Alzheimer's disease and spinal cord injury mouse models.
PubMed: 36262561
DOI: 10.12703/r-01-0000017