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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 -
Nature Communications Jan 2024Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy...
Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy supplies are perturbed. Mitochondria are stabilized near synapses via the cytoskeleton and provide the local energy required for synaptic plasticity. However, the mechanisms that tether and stabilize mitochondria to support synaptic plasticity are unknown. We identified proteins exclusively tethering mitochondria to actin near postsynaptic spines. We find that VAP, the vesicle-associated membrane protein-associated protein implicated in amyotrophic lateral sclerosis, stabilizes mitochondria via actin near the spines. To test if the VAP-dependent stable mitochondrial compartments can locally support synaptic plasticity, we used two-photon glutamate uncaging for spine plasticity induction and investigated the induced and adjacent uninduced spines. We find VAP functions as a spatial stabilizer of mitochondrial compartments for up to ~60 min and as a spatial ruler determining the ~30 μm dendritic segment supported during synaptic plasticity.
Topics: Actins; Dendritic Spines; Neuronal Plasticity; Synapses; Mitochondria
PubMed: 38177103
DOI: 10.1038/s41467-023-44233-8 -
BioEssays : News and Reviews in... Jul 2024Long-term potentiation (LTP) of excitatory synapses is a leading model to explain the concept of information storage in the brain. Multiple mechanisms contribute to LTP,... (Review)
Review
Long-term potentiation (LTP) of excitatory synapses is a leading model to explain the concept of information storage in the brain. Multiple mechanisms contribute to LTP, but central amongst them is an increased sensitivity of the postsynaptic membrane to neurotransmitter release. This sensitivity is predominantly determined by the abundance and localization of AMPA-type glutamate receptors (AMPARs). A combination of AMPAR structural data, super-resolution imaging of excitatory synapses, and an abundance of electrophysiological studies are providing an ever-clearer picture of how AMPARs are recruited and organized at synaptic junctions. Here, we review the latest insights into this process, and discuss how both cytoplasmic and extracellular receptor elements cooperate to tune the AMPAR response at the hippocampal CA1 synapse.
Topics: Receptors, AMPA; Animals; Humans; Synapses; Long-Term Potentiation; Synaptic Transmission; CA1 Region, Hippocampal
PubMed: 38693811
DOI: 10.1002/bies.202400006 -
Neuropharmacology Nov 2023Insulin plays roles in brain functions such as neural development and plasticity and is reported to be involved in dementia and depression. However, little information...
Insulin plays roles in brain functions such as neural development and plasticity and is reported to be involved in dementia and depression. However, little information is available on the insulin-mediated modulation of electrophysiological activities, especially in the cerebral cortex. This study examined how insulin modulates the neural activities of inhibitory neurons and inhibitory postsynaptic currents (IPSCs) in rat insular cortex (IC; either sex) by multiple whole-cell patch-clamp recordings. We demonstrated that insulin increased the repetitive spike firing rate with a decrease in the threshold potential without changing the resting membrane potentials and input resistance of fast-spiking GABAergic neurons (FSNs). Next, we found a dose-dependent enhancement of unitary IPSCs (uIPSCs) by insulin in the connections from FSNs to pyramidal neurons (PNs). The insulin-induced enhancement of uIPSCs accompanied decreases in the paired-pulse ratio, suggesting that insulin increases GABA release from presynaptic terminals. The finding of miniature IPSC recordings of the increased frequency without changing the amplitude supports this hypothesis. Insulin had little effect on uIPSCs under the coapplication of S961, an insulin receptor antagonist, or lavendustin A, an inhibitor of tyrosine kinase. The PI3-K inhibitor wortmannin or the PKB/Akt inhibitors, deguelin and Akt inhibitor VIII, blocked the insulin-induced enhancement of uIPSCs. Intracellular application of Akt inhibitor VIII to presynaptic FSNs also blocked insulin-induced enhancement of uIPSCs. In contrast, uIPSCs were enhanced by insulin in combination with the MAPK inhibitor PD98059. These results suggest that insulin facilitates the inhibition of PNs by increases in FSN firing frequency and IPSCs from FSNs to PNs. (250 words).
Topics: Rats; Animals; Insular Cortex; Insulin; Rats, Transgenic; Pyramidal Cells; GABAergic Neurons; Synaptic Transmission; Inhibitory Postsynaptic Potentials
PubMed: 37393988
DOI: 10.1016/j.neuropharm.2023.109649 -
Neural Networks : the Official Journal... Oct 2023As a member of the third generation of artificial neural network models, spiking neural P systems (SN P systems) have gained a hot research spot in recent years. This...
As a member of the third generation of artificial neural network models, spiking neural P systems (SN P systems) have gained a hot research spot in recent years. This work introduces the phenomenon of lateral inhibition in biological nervous systems into SN P systems, and proposes SN P systems with lateral inhibition (LISN P systems). LISN P systems add the property of synaptic length to portray the lateral distance between neurons, and adopt a new form of rules, lateral interaction rules, to describe the reception of spikes by postsynaptic neurons with different lateral distances from the presynaptic neuron. Specifically, an excited neuron produces lateral inhibition on surrounding postsynaptic neurons. Postsynaptic neurons close to the excited neuron, i.e., neurons with small lateral distances, are more susceptible to lateral inhibition and either receive a fewer number of spikes generated by the excited neuron or fail to receive spikes. As the lateral distance increases, the lateral inhibition weakens, and the number of spikes received by postsynaptic neurons increases. Based on the above mechanism, four specific LISN P systems are designed for generating arbitrary odd numbers, arbitrary even numbers, arbitrary natural numbers and arithmetic series, respectively, as examples. By designing working modules, LISN P systems provide equivalence in computational power to the universal register machines in both generating and accepting modes. This verifies the computational completeness of LISN P systems. A universal LISN P system using merely 65 neurons is devised for function computation. According to comparisons among several systems, universal LISN P systems require fewer computational resources.
Topics: Models, Neurological; Action Potentials; Neural Networks, Computer; Neurons
PubMed: 37619512
DOI: 10.1016/j.neunet.2023.08.013 -
Neurobiology of Disease Aug 2023Children with Down syndrome (DS, trisomy of chromosome 21) have an increased risk of infantile spasms (IS). As an epileptic encephalopathy, IS may further impair...
Children with Down syndrome (DS, trisomy of chromosome 21) have an increased risk of infantile spasms (IS). As an epileptic encephalopathy, IS may further impair cognitive function and exacerbate neurodevelopmental delays already present in children with DS. To investigate the pathophysiology of IS in DS, we induced IS-like epileptic spasms in a genetic mouse model of DS that carries human chromosome 21q, TcMAC21, the animal model most closely representing gene dosage imbalance in DS. Repetitive extensor/flexor spasms were induced by the GABA receptor agonist γ-butyrolactone (GBL) and occurred predominantly in young TcMAC21 mice (85%) but also in some euploid mice (25%). During GBL application, background electroencephalographic (EEG) amplitude was reduced, and rhythmic, sharp-and-slow wave activity or high-amplitude burst (epileptiform) events emerged in both TcMAC21 and euploid mice. Spasms occurred only during EEG bursts, but not every burst was accompanied by a spasm. Electrophysiological experiments revealed that basic membrane properties (resting membrane potential, input resistance, action-potential threshold and amplitude, rheobase, input-output relationship) of layer V pyramidal neurons were not different between TcMAC21 mice and euploid controls. However, excitatory postsynaptic currents (EPSCs) evoked at various intensities were significantly larger in TcMAC21 mice than euploid controls, while inhibitory postsynaptic currents (IPSCs) were similar between the two groups, resulting in an increased excitation-inhibition (E-I) ratio. These data show that behavioral spasms with epileptic EEG activity can be induced in young TcMAC21 DS mice, providing proof-of-concept evidence for increased IS susceptibility in these DS mice. Our findings also show that basic membrane properties are similar in TcMAC21 and euploid mice, while the neocortical E-I balance is altered to favor increased excitation in TcMAC21 mice, which may predispose to IS generation.
Topics: Humans; Child; Mice; Animals; Spasms, Infantile; Down Syndrome; Neocortex; Spasm; Epilepsy; GABA-B Receptor Agonists; Electroencephalography; Disease Models, Animal
PubMed: 37315904
DOI: 10.1016/j.nbd.2023.106198 -
BioRxiv : the Preprint Server For... Nov 2023Rapid delivery of glutamate receptors to the postsynaptic membrane via vesicle fusion is a central component of synaptic plasticity. However, it is unknown how this...
Rapid delivery of glutamate receptors to the postsynaptic membrane via vesicle fusion is a central component of synaptic plasticity. However, it is unknown how this process supports specific neural computations during behavior. To bridge this gap, we combined conditional genetic deletion of a component of the postsynaptic membrane fusion machinery, Syntaxin3 (Stx3), in hippocampal CA1 neurons of mice with population calcium imaging. This approach revealed that Stx3 is necessary for forming the neural dynamics that support novelty processing, spatial reward memory and offline memory consolidation. In contrast, CA1 Stx3 was dispensable for maintaining aspects of the neural code that exist presynaptic to CA1 such as representations of context and space. Thus, manipulating postsynaptic membrane fusion identified computations that specifically require synaptic restructuring via membrane trafficking in CA1 and distinguished them from neural representation that could be inherited from upstream brain regions or learned through other mechanisms.
PubMed: 38045362
DOI: 10.1101/2023.11.20.567978 -
Molecular & Cellular Proteomics : MCP Nov 2023The postsynaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands of proteins and is a key node in the regulation of...
The postsynaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands of proteins and is a key node in the regulation of synaptic plasticity. To gain new mechanistic insight into experience-induced changes in the PSD, we examined the global dynamics of the hippocampal PSD proteome and phosphoproteome in mice following four different types of experience. Mice were trained using an inhibitory avoidance (IA) task and hippocampal PSD fractions were isolated from individual mice to investigate molecular mechanisms underlying experience-dependent remodeling of synapses. We developed a new strategy to identify and quantify the relatively low level of site-specific phosphorylation of PSD proteome from the hippocampus, by using a modified iTRAQ-based TiSH protocol. In the PSD, we identified 3938 proteins and 2761 phosphoproteins in the sequential strategy covering a total of 4968 unique protein groups (at least two peptides including a unique peptide). On the phosphoproteins, we identified a total of 6188 unambiguous phosphosites (75%
Topics: Mice; Animals; Proteome; Membrane Proteins; Nerve Tissue Proteins; Hippocampus; Synapses; Peptides; Phosphoproteins; Disks Large Homolog 4 Protein
PubMed: 37806341
DOI: 10.1016/j.mcpro.2023.100661 -
Biochemical Society Transactions Dec 2023The PDZ and LIM domain (PDLIM) proteins are associated with the actin cytoskeleton and have conserved in roles in metazoan actin organisation and function. They... (Review)
Review
The PDZ and LIM domain (PDLIM) proteins are associated with the actin cytoskeleton and have conserved in roles in metazoan actin organisation and function. They primarily function as scaffolds linking various proteins to actin and its binding partner α-actinin via two conserved domains; an N-terminal postsynaptic density 95, discs large and zonula occludens-1 (PDZ) domain, and either single or multiple C-terminal LIN-11, Isl-1 and MEC-3 (LIM) domains in the actinin-associated LIM protein (ALP)- and Enigma-related proteins, respectively. While their role in actin organisation, such as in stress fibres or in the Z-disc of muscle fibres is well known, emerging evidence also suggests a role in actin-dependent membrane trafficking in the endosomal system. This is mediated by a recently identified interaction with the sorting nexin 17 (SNX17) protein, an adaptor for the trafficking complex Commander which is itself intimately linked to actin-directed formation of endosomal recycling domains. In this review we focus on the currently understood structural basis for PDLIM function. The PDZ domains mediate direct binding to distinct classes of PDZ-binding motifs (PDZbms), including α-actinin and other actin-associated proteins, and a highly specific interaction with the type III PDZbm such as the one found in the C-terminus of SNX17. The structures of the LIM domains are less well characterised and how they engage with their ligands is completely unknown. Despite the lack of experimental structural data, we find that recently developed machine learning-based structure prediction methods provide insights into their potential interactions and provide a template for further studies of their molecular functions.
Topics: Animals; Actins; Actinin; PDZ Domains; Actin Cytoskeleton; LIM Domain Proteins; Protein Binding
PubMed: 38095060
DOI: 10.1042/BST20220804 -
Pharmaceutics May 2024Myasthenia gravis (MG) is a rare chronic autoimmune disease caused by the production of autoantibodies against the postsynaptic membrane receptors present at the... (Review)
Review
Myasthenia gravis (MG) is a rare chronic autoimmune disease caused by the production of autoantibodies against the postsynaptic membrane receptors present at the neuromuscular junction. This condition is characterized by fatigue and muscle weakness, including diplopia, ptosis, and systemic impairment. Emerging evidence suggests that in addition to immune dysregulation, the pathogenesis of MG may involve mitochondrial damage and ferroptosis. Mitochondria are the primary site of energy production, and the reactive oxygen species (ROS) generated due to mitochondrial dysfunction can induce ferroptosis. Nanomedicines have been extensively employed to treat various disorders due to their modifiability and good biocompatibility, but their application in MG management has been rather limited. Nevertheless, nanodrug delivery systems that carry immunomodulatory agents, anti-oxidants, or ferroptosis inhibitors could be effective for the treatment of MG. Therefore, this review focuses on various nanoplatforms aimed at attenuating immune dysregulation, restoring mitochondrial function, and inhibiting ferroptosis that could potentially serve as promising agents for targeted MG therapy.
PubMed: 38794313
DOI: 10.3390/pharmaceutics16050651