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Neuroscience Letters Oct 2019At vertebrate motor endplates, the conversion of nerve impulses into muscle contraction is initiated by binding of acetylcholine to its nicotinic receptor (nAChR) at the... (Review)
Review
At vertebrate motor endplates, the conversion of nerve impulses into muscle contraction is initiated by binding of acetylcholine to its nicotinic receptor (nAChR) at the postsynapse. Efficiency and safety of this process are dependent on proper localization, density, and molecular composition of the receptors. To warrant this, intricate machineries regulating the turnover of nAChR are in place. They control and execute the processes of i) expression, ii) delivery to the postsynaptic membrane, iii) clustering at the plasma membrane, iv) endocytic retrieval, v) activity-dependent recycling, and vi) degradation of nAChR. Concentrating on aspects iv-vi, this review addresses the current status of techniques, concepts, and open questions on endocytosis, recycling, and degradation of nAChR. A picture is emerging, that shows connections between executing machineries and their regulators. The first group includes the actin cytoskeleton, myosin motor proteins, Rab G-proteins, and the autophagic cascade. The second group features protein kinases A and C, Cdk5, and CaMKII as well as other components like the E3-ligase MuRF1 and the membrane shaping regulator, SH3GLB1. Recent studies have started to shed light onto nerve inputs that appear to master the tuning of the postsynaptic protein trafficking apparatus and the expression of critical components for nAChR turnover.
Topics: Animals; Endocytosis; Humans; Motor Endplate; Receptors, Nicotinic
PubMed: 31421156
DOI: 10.1016/j.neulet.2019.134434 -
Amino Acids Dec 2020Synaptosomes are frequently used research objects in neurobiology studies focusing on synaptic transmission as they mimic several aspects of the physiological synaptic...
Synaptosomes are frequently used research objects in neurobiology studies focusing on synaptic transmission as they mimic several aspects of the physiological synaptic functions. They contain the whole apparatus for neurotransmission, the presynaptic nerve ending with synaptic vesicles, synaptic mitochondria and often a segment of the postsynaptic membrane along with the postsynaptic density is attached to its outer surface. As being artificial functional organelles, synaptosomes are viable for several hours, retain their activity, membrane potential, and capable to store, release, and reuptake neurotransmitters. Synaptosomes are ideal subjects for proteomic analysis. The recently available separation and protein detection techniques can cope with the reduced complexity of the organelle and enable the simultaneous qualitative and quantitative analysis of thousands of proteins shaping the structural and functional characteristics of the synapse. Synaptosomes are formed during the homogenization of nervous tissue in the isoosmotic milieu and can be isolated from the homogenate by various approaches. Each enrichment method has its own benefits and drawbacks and there is not a single method that is optimal for all research purposes. For a proper proteomic experiment, it is desirable to preserve the native synaptic structure during the isolation procedure and keep the degree of contamination from other organelles or cell types as low as possible. In this article, we examined five synaptosome isolation methods from a proteomic point of view by the means of electron microscopy, Western blot, and liquid chromatography-mass spectrometry to compare their efficiency in the isolation of synaptosomes and depletion of contaminating subcellular structures. In our study, the different isolation procedures led to a largely overlapping pool of proteins with a fairly similar distribution of presynaptic, active zone, synaptic vesicle, and postsynaptic proteins; however, discrete differences were noticeable in individual postsynaptic proteins and in the number of identified transmembrane proteins. Much pronounced variance was observed in the degree of contamination with mitochondrial and glial structures. Therefore, we suggest that in selecting the appropriate isolation method for any neuroproteomics experiment carried out on synaptosomes, the degree and sort/source of contamination should be considered as a primary aspect.
Topics: Animals; Brain; Chromatography, Liquid; Humans; Mass Spectrometry; Membrane Potentials; Membrane Proteins; Microscopy, Electron; Mitochondria; Presynaptic Terminals; Proteomics; Rats; Synapses; Synaptic Transmission; Synaptosomes
PubMed: 33211194
DOI: 10.1007/s00726-020-02912-6 -
The Journal of General Physiology Apr 2021Spines are tiny nanoscale protrusions from dendrites of neurons. In the cortex and hippocampus, most of the excitatory postsynaptic sites reside in spines. The bulbous... (Review)
Review
Spines are tiny nanoscale protrusions from dendrites of neurons. In the cortex and hippocampus, most of the excitatory postsynaptic sites reside in spines. The bulbous spine head is connected to the dendritic shaft by a thin membranous neck. Because the neck is narrow, spine heads are thought to function as biochemically independent signaling compartments. Thus, dynamic changes in the composition, distribution, mobility, conformations, and signaling properties of molecules contained within spines can account for much of the molecular basis of postsynaptic function and regulation. A major factor in controlling these changes is the diffusional properties of proteins within this small compartment. Advances in measurement techniques using fluorescence microscopy now make it possible to measure molecular diffusion within single dendritic spines directly. Here, we review the regulatory mechanisms of diffusion in spines by local intra-spine architecture and discuss their implications for neuronal signaling and synaptic plasticity.
Topics: Dendritic Spines; Diffusion; Hippocampus; Neuronal Plasticity; Neurons; Synapses
PubMed: 33720306
DOI: 10.1085/jgp.202012814 -
Proceedings of the National Academy of... Nov 2022Robust neural information transfer relies on a delicate molecular nano-architecture of chemical synapses. Neurotransmitter release is controlled by a specific...
Robust neural information transfer relies on a delicate molecular nano-architecture of chemical synapses. Neurotransmitter release is controlled by a specific arrangement of proteins within presynaptic active zones. How the specific presynaptic molecular architecture relates to postsynaptic organization and how synaptic nano-architecture is transsynaptically regulated to enable stable synaptic transmission remain enigmatic. Using time-gated stimulated emission-depletion microscopy at the neuromuscular junction, we found that presynaptic nanorings formed by the active-zone scaffold Bruchpilot (Brp) align with postsynaptic glutamate receptor (GluR) rings. Individual rings harbor approximately four transsynaptically aligned Brp-GluR nanocolumns. Similar nanocolumn rings are formed by the presynaptic protein Unc13A and GluRs. Intriguingly, acute GluR impairment triggers transsynaptic nanocolumn formation on the minute timescale during homeostatic plasticity. We reveal distinct phases of structural transsynaptic homeostatic plasticity, with postsynaptic GluR reorganization preceding presynaptic Brp modulation. Finally, homeostatic control of transsynaptic nano-architecture and neurotransmitter release requires the auxiliary GluR subunit Neto. Thus, transsynaptic nanocolumn rings provide a substrate for rapid homeostatic stabilization of synaptic efficacy.
Topics: Animals; Neuromuscular Junction; Drosophila; Synaptic Transmission; Synapses; Receptors, Glutamate; Drosophila Proteins; Neurotransmitter Agents; Membrane Proteins
PubMed: 36322725
DOI: 10.1073/pnas.2119044119 -
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 -
Neuroscience Nov 2019Soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins mediate membrane fusion events in eukaryotic cells. Traditionally recognized as... (Review)
Review
Soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins mediate membrane fusion events in eukaryotic cells. Traditionally recognized as major players in regulating presynaptic neurotransmitter release, accumulative evidence over recent years has identified several SNARE proteins implicated in important postsynaptic processes such as neurotransmitter receptor trafficking and synaptic plasticity. Here we analyze the emerging data revealing this novel functional dimension for SNAREs with a focus on the molecular specialization of vesicular recycling and fusion in dendrites compared to those at axon terminals and its impact in synaptic transmission and plasticity.
Topics: Animals; Humans; Neuronal Plasticity; Neurons; SNARE Proteins; Synaptic Transmission
PubMed: 30458218
DOI: 10.1016/j.neuroscience.2018.11.012 -
Neuropharmacology Aug 2023Early life stress (ELS) alters the excitation-inhibition-balance (EI-balance) in various rodent brain areas and may be responsible for behavioral impairment later in...
Early life stress (ELS) alters the excitation-inhibition-balance (EI-balance) in various rodent brain areas and may be responsible for behavioral impairment later in life. The EI-balance is (amongst others) influenced by the switch of GABAergic transmission from excitatory to inhibitory, the so-called "GABA-switch". Here, we investigated how ELS affects the GABA-switch in mouse infralimbic Prefrontal Cortex layer 2/3 neurons, using the limited-nesting-and-bedding model. In ELS mice, the GABA-switch occurred already between postnatal day (P) 6 and P9, as opposed to P15-P21 in controls. This was associated with increased expression of the inward chloride transporter NKCC1, compared to the outward chloride transporter KCC2, both of which are important for the intracellular chloride concentration and, hence, the GABA reversal potential (Erev). Chloride transporters are not only important for regulating chloride concentration postsynaptically, but also presynaptically. Depending on the Erev of GABA, presynaptic GABA receptor stimulation causes a depolarization or hyperpolarization, and thereby enhanced or reduced fusion of glutamate vesicles respectively, in turn changing the frequency of miniature postsynaptic currents (mEPSCs). In accordance, bumetanide, a blocker of NKCC1, shifted the Erev GABA towards more hyperpolarized levels in P9 control mice and reduced the mEPSC frequency. Other modulators of chloride transporters, e.g. VU0463271 (a KCC2 antagonist) and aldosterone -which increases NKCC1 expression-did not affect postsynaptic Erev in ELS P9 mice, but did increase the mEPSC frequency. We conclude that the mouse GABA-switch is accelerated after ELS, affecting both the pre- and postsynaptic chloride homeostasis, the former altering glutamatergic transmission. This may considerably affect brain development.
Topics: Animals; Mice; Acceleration; Chlorides; gamma-Aminobutyric Acid; Membrane Transport Proteins; Receptors, GABA-A; Symporters; Stress, Physiological
PubMed: 37061088
DOI: 10.1016/j.neuropharm.2023.109543 -
Frontiers in Physiology 2021Synaptic plasticity is a cellular mechanism of learning and memory. The synaptic strength can be persistently upregulated or downregulated to update the information sent... (Review)
Review
Synaptic plasticity is a cellular mechanism of learning and memory. The synaptic strength can be persistently upregulated or downregulated to update the information sent to the neuronal network and form a memory engram. For its molecular mechanism, the stability of α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate-type glutamate receptor (AMPAR), a glutamatergic ionotropic receptor, on the postsynaptic membrane has been studied for these two decades. Since AMPAR is not saturated on the postsynaptic membrane during a single event of neurotransmitter release, the number and nanoscale localization of AMPAR is critical for regulating the efficacy of synaptic transmission. The observation of AMPAR on the postsynaptic membrane by super-resolution microscopy revealed that AMPAR forms a nanodomain that is defined as a stable segregated cluster on the postsynaptic membrane to increase the efficacy of synaptic transmission. Postsynaptic density (PSD), an intracellular protein condensate underneath the postsynaptic membrane, regulates AMPAR dynamics the intracellular domain of Stargazin, an auxiliary subunit of AMPAR. Recently, it was reported that PSD is organized by liquid-liquid phase separation (LLPS) to form liquid-like protein condensates. Furthermore, the calcium signal induced by the learning event triggers the persistent formation of sub-compartments of different protein groups inside protein condensates. This explains the formation of nanodomains synaptic activation. The liquid-like properties of LLPS protein condensates are ideal for the molecular mechanism of synaptic plasticity. In this review, we summarize the recent progress in the properties and regulation of synaptic plasticity, postsynaptic receptors, PSD, and LLPS.
PubMed: 34975543
DOI: 10.3389/fphys.2021.795757 -
Cognitive Neurodynamics Apr 2021Synaptic transmission is the key system for the information transfer and elaboration among neurons. Nevertheless, a synapse is not a standing alone structure but it is a...
Synaptic transmission is the key system for the information transfer and elaboration among neurons. Nevertheless, a synapse is not a standing alone structure but it is a part of a population of synapses inputting the information from several neurons on a specific area of the dendritic tree of a single neuron. This population consists of excitatory and inhibitory synapses the inputs of which drive the postsynaptic membrane potential in the depolarizing (excitatory synapses) or depolarizing (inhibitory synapses) direction modulating in such a way the postsynaptic membrane potential. The postsynaptic response of a single synapse depends on several biophysical factors the most important of which is the value of the membrane potential at which the response occurs. The concurrence in a specific time window of inputs by several synapses located in a specific area of the dendritic tree can, consequently, modulate the membrane potential such to severely influence the single postsynaptic response. The degree of modulation operated by the synaptic population depends on the number of synapses active, on the relative proportion between excitatory and inbibitory synapses belonging to the population and on their specific mean firing frequencies. In the present paper we show results obtained by the simulation of the activity of a single Glutamatergic excitatory synapse under the influence of two different populations composed of the same proportion of excitatory and inhibitory synapses but having two different sizes (total number of synapses). The most relevant conclusion of the present simulations is that the information transferred by the single synapse is not and independent simple transition between a pre- and a postsynaptic neuron but is the result of the cooperation of all the synapses which concurrently try to transfer the information to the postsynaptic neuron in a given time window. This cooperativeness is mainly operated by a simple mechanism of modulation of the postsynaptic membrane potential which influences the amplitude of the different components forming the postsynaptic excitatory response.
PubMed: 33854645
DOI: 10.1007/s11571-020-09607-4 -
Frontiers in Cellular Neuroscience 2019Until recently, glial cells have been considered mainly support cells for neurons in the mammalian brain. However, many studies have unveiled a variety of glial... (Review)
Review
Until recently, glial cells have been considered mainly support cells for neurons in the mammalian brain. However, many studies have unveiled a variety of glial functions including electrolyte homeostasis, inflammation, synapse formation, metabolism, and the regulation of neurotransmission. The importance of these functions illuminates significant crosstalk between glial and neuronal cells. Importantly, it is known that astrocytes secrete signals that can modulate both presynaptic and postsynaptic function. It is also known that the lipid compositions of the pre- and post-synaptic membranes of neurons greatly impact functions such as vesicle fusion and receptor mobility. These data suggest an essential lipid-mediated communication between glial cells and neurons. Little is known, however, about how the lipid metabolism of both cell types may interact. In this review, we discuss neuronal and glial lipid metabolism and suggest how they might interact to impact neurotransmission.
PubMed: 31164804
DOI: 10.3389/fncel.2019.00212