-
Frontiers in Neurology 2015Correct function of neuronal networks is enabled by a delicate interplay among neurons communicating with each other. One of the keys is the communication at chemical... (Review)
Review
Correct function of neuronal networks is enabled by a delicate interplay among neurons communicating with each other. One of the keys is the communication at chemical synapses where neurotransmitters like glutamate, GABA, and glycine enable signal transfer over the synaptic cleft. Thereby, the neurotransmitters are released from the presynapse and bind as ligands to specific receptors at the postsynaptic side to allow for modulation of the postsynaptic membrane potentials. The postsynaptic electrical signal, which is highly modulated by voltage-gated ion channels, spreads over the dendritic tree and is thus integrated to allow for generation of action potentials at the axon hillock. This concert of receptors and voltage-gated ion channels depends on correct function of all its components. Misfunction of receptors and/or voltage-gated potassium channels (VGKC) leads to diverse adverse effects in patients. Such malfunctions can be the result of inherited genetic alterations or pharmacological side effects by drugs. Recently, autoantibodies targeting receptor or channel complexes like NMDAR, AMPAR, GABA-receptors, glycine receptors, LGI1 or CASPR2 (previously termed as VGKC-complex antibodies) have been discovered. The presence of specific autoantibodies against these targets associates with severe forms of antibody-mediated encephalitis. Understanding the molecular details of autoantibody actions on receptor and VGKC complexes is highly desirable and may open the path to develop specific therapies to treat humoral autoimmune encephalitis. Here, we summarize the current knowledge and discuss technical approaches to fill the gap of knowledge. These techniques include electrophysiology, biochemical approaches for epitope mapping, and in silico modeling to simulate molecular interactions between autoantibody and its molecular target.
PubMed: 26217297
DOI: 10.3389/fneur.2015.00149 -
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 -
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 -
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 -
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 -
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 -
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 -
Cell Reports Feb 2016The dynamic interactions between synaptic excitation and inhibition (E/I) shape membrane potential fluctuations and determine patterns of neuronal outputs; however, the...
The dynamic interactions between synaptic excitation and inhibition (E/I) shape membrane potential fluctuations and determine patterns of neuronal outputs; however, the spatiotemporal organization of these interactions within a single cell is poorly understood. Here, we investigated the relationship between local synaptic excitation and global inhibition in hippocampal pyramidal neurons using functional dendrite imaging in combination with whole-cell recordings of inhibitory postsynaptic currents. We found that the sums of spine inputs over dendritic trees were counterbalanced by a proportional amount of somatic inhibitory inputs. This online E/I correlation was maintained in dendritic segments that were longer than 50 μm. However, at the single spine level, only 22% of the active spines were activated with inhibitory inputs. This inhibition-coupled activity occurred mainly in the spines with large heads. These results shed light on a microscopic E/I-balancing mechanism that operates at selected synapses and that may increase the accuracy of neural information.
Topics: Animals; Animals, Newborn; Dendritic Spines; Excitatory Postsynaptic Potentials; Hippocampus; Inhibitory Postsynaptic Potentials; Patch-Clamp Techniques; Pyramidal Cells; Rats; Rats, Wistar; Single-Cell Analysis; Synapses; Tissue Culture Techniques
PubMed: 26854220
DOI: 10.1016/j.celrep.2016.01.024 -
Biomolecules & Biomedicine Sep 2023Rapsyn, an intracellular scaffolding protein associated with the postsynaptic membranes in the neuromuscular junction (NMJ), is critical for nicotinic acetylcholine... (Review)
Review
Rapsyn, an intracellular scaffolding protein associated with the postsynaptic membranes in the neuromuscular junction (NMJ), is critical for nicotinic acetylcholine receptor clustering and maintenance. Therefore, Rapsyn is essential to the NMJ formation and maintenance, and Rapsyn mutant is one of the reasons causing the pathogenies of congenital myasthenic syndrome (CMS). In addition, there is little research on Rapsyn in the central nervous system (CNS). In this review, the role of Rapsyn in the NMJ formation and the mutation of Rapsyn leading to CMS will be reviewed separately and sequentially. Finally, the potential function of Rapsyn is prospected.
Topics: Humans; Myasthenic Syndromes, Congenital; Receptors, Cholinergic; Neuromuscular Junction; Muscle Proteins
PubMed: 36815443
DOI: 10.17305/bb.2022.8641