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Handbook of Clinical Neurology 2023Myasthenia gravis is an autoimmune disorder caused by antibodies against elements in the postsynaptic membrane at the neuromuscular junction, which leads to muscle... (Review)
Review
Myasthenia gravis is an autoimmune disorder caused by antibodies against elements in the postsynaptic membrane at the neuromuscular junction, which leads to muscle weakness. Congenital myasthenic syndromes are rare and caused by mutations affecting pre- or postsynaptic function at the neuromuscular synapse and resulting in muscle weakness. MG has a prevalence of 150-250 and an annual incidence of 8-10 individuals per million. The majority has disease onset after age 50 years. Juvenile MG with onset in early childhood is more common in East Asia. MG is subgrouped according to type of pathogenic autoantibodies, age of onset, thymus pathology, and generalization of muscle weakness. More than 80% have antibodies against the acetylcholine receptor. The remaining have antibodies against MuSK, LRP4, or postsynaptic membrane antigens not yet identified. A thymoma is present in 10% of MG patients, and more than one-third of thymoma patients develop MG as a paraneoplastic condition. Immunosuppressive drug therapy, thymectomy, and symptomatic drug therapy with acetylcholine esterase inhibitors represent cornerstones in the treatment. The prognosis is good, with the majority of patients having mild or moderate symptoms only. Most congenital myasthenic syndromes are due to dysfunction in the postsynaptic membrane. Symptom debut is in early life. Symptomatic drug treatment has sometimes a positive effect.
Topics: Child, Preschool; Humans; Middle Aged; Myasthenic Syndromes, Congenital; Thymoma; Myasthenia Gravis; Muscle Weakness; Autoantibodies; Thymus Neoplasms
PubMed: 37562891
DOI: 10.1016/B978-0-323-98818-6.00010-8 -
Molecular and Cellular Neurosciences Mar 2023Molecular interactions between pre- and postsynaptic membranes play critical roles during the development, function and maintenance of synapses. Synaptic interactions... (Review)
Review
Molecular interactions between pre- and postsynaptic membranes play critical roles during the development, function and maintenance of synapses. Synaptic interactions are mediated by cell surface receptors that may be held in place by trans-synaptic adhesion or intracellular binding to membrane-associated scaffolding and signaling complexes. Despite their role in stabilizing synaptic contacts, synaptic adhesion molecules undergo turnover and degradation during all stages of a neuron's life. Here we review current knowledge about membrane trafficking mechanisms that regulate turnover of synaptic adhesion molecules and the functional significance of turnover for synapse development and function. Based on recent proteomics, genetics and imaging studies, synaptic adhesion molecules exhibit remarkably high turnover rates compared to other synaptic proteins. Degradation occurs predominantly via endolysosomal mechanisms, with little evidence for roles of proteasomal or autophagic degradation. Basal turnover occurs both during synaptic development and maintenance. Neuronal activity typically stabilizes synaptic adhesion molecules while downregulating neurotransmitter receptors based on turnover. In conclusion, constitutive turnover of synaptic adhesion molecules is not a necessarily destabilizing factor, but a basis for the dynamic regulation of trans-synaptic interactions during synapse formation and maintenance.
Topics: Synapses; Synaptic Membranes; Neurons; Cell Adhesion; Signal Transduction; Cell Adhesion Molecules, Neuronal
PubMed: 36649812
DOI: 10.1016/j.mcn.2023.103816 -
Neuropharmacology Jun 2020The flexibility of neuronal networks is believed to rely mainly on the plasticity of excitatory synapses. However, like their excitatory counterparts, inhibitory... (Review)
Review
The flexibility of neuronal networks is believed to rely mainly on the plasticity of excitatory synapses. However, like their excitatory counterparts, inhibitory synapses also undergo several forms of synaptic plasticity. This review examines recent advances in the understanding of the molecular mechanisms leading to postsynaptic GABAergic plasticity. Specifically, modulation of GABAA receptor (GABAAR) number at postsynaptic sites plays a key role, with the interaction of GABAARs with the scaffold protein gephyrin and other postsynaptic scaffold/regulatory proteins having particular importance. Our understanding of these molecular interactions are progressing, based on recent insights into the processes of GABAAR lateral diffusion, gephyrin dynamics, and gephyrin nanoscale organization. This article is part of the special issue entitled 'Mobility and trafficking of neuronal membrane proteins'.
Topics: Animals; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; Humans; Membrane Proteins; Neuronal Plasticity; Receptors, GABA-A; Synapses; Synaptic Potentials
PubMed: 31108109
DOI: 10.1016/j.neuropharm.2019.05.020 -
Neuroscience Feb 2021The postsynaptic density (PSD) is a complex subcellular domain important for postsynaptic signaling, function, and plasticity. The PSD is present at excitatory synapses... (Review)
Review
The postsynaptic density (PSD) is a complex subcellular domain important for postsynaptic signaling, function, and plasticity. The PSD is present at excitatory synapses and specialized to allow for precise neuron-to-neuron transmission of information. The PSD is localized immediately underneath the postsynaptic membrane forming a major protein network that regulates postsynaptic signaling and synaptic plasticity. Glutamatergic synaptic dysfunction affecting PSD morphology and signaling events have been described in many neurodegenerative disorders, either sporadic or familial forms. Thus, in this review we describe the main protein players forming the PSD and their activity, as well as relevant modifications in key components of the postsynaptic architecture occurring in Huntington's, Parkinson's and Alzheimer's diseases.
Topics: Humans; Neurodegenerative Diseases; Neuronal Plasticity; Post-Synaptic Density; Synapses; Synaptic Transmission
PubMed: 31887357
DOI: 10.1016/j.neuroscience.2019.12.002 -
Neuroscience Nov 2019SNARE-complexes drive the fusion of membrane-bound vesicles with target membranes or with each other (homotypic fusion). The SNARE-proteins are subdivided into Q, Q, Q... (Review)
Review
SNARE-complexes drive the fusion of membrane-bound vesicles with target membranes or with each other (homotypic fusion). The SNARE-proteins are subdivided into Q, Q, Q and R-SNAREs depending on their position in the four-helical SNARE-bundle. Here, we review the SNAP-25 protein sub-family, which includes both the Q and Q SNARE-domains within a single protein. In vertebrates, this sub-family consists of SNAP-25, SNAP-23, SNAP-29 and SNAP-47, named for their apparent molecular weights. SNAP-25 and SNAP-23 are specialized for driving regulated exocytosis. SNAP-25 performs this function in the nervous system, and in neuroendocrine cells, where fast Ca-dependent triggering is required in order to synchronize release with an electrical signal, whereas SNAP-23 drives regulated exocytosis in most other cases that have been studied, e.g. platelet exocytosis or glucose transporter trafficking. SNAP-25 is regulated by alternative splicing, phosphorylation and by G-protein binding, and it regulates Ca-channels, neuronal survival and postsynaptic spine development. SNAP-23 is primarily regulated by phosphorylation within the linker connecting Q to Q. Cross-rescue experiments show that SNAP-25 and SNAP-23 can (at least partly) substitute for each other, whereas SNAP-29 and SNAP-47 cannot. SNAP-29 is present on intracellular membranes and performs functions in autophagosome-to-lysosome fusion, among others. An overlapping function for SNAP-47 was described; in addition, SNAP-47 mediates postsynaptic AMPA-receptor insertion. Overall, the presence of two SNARE-domains confers members of this family the ability to associate to different Q and R-SNAREs and drive diverse membrane fusion reactions; one member of the family, SNAP-25, has been devoted entirely to Ca-triggered fusion and has taken on a number of additional, regulatory roles.
Topics: Animals; Exocytosis; Humans; Neurons; Synaptosomal-Associated Protein 25
PubMed: 30267828
DOI: 10.1016/j.neuroscience.2018.09.020 -
Frontiers in Neural Circuits 2021Dendritic spines, the distinctive postsynaptic feature of central nervous system (CNS) excitatory synapses, have been studied extensively as electrical and chemical... (Review)
Review
Dendritic spines, the distinctive postsynaptic feature of central nervous system (CNS) excitatory synapses, have been studied extensively as electrical and chemical compartments, as well as scaffolds for receptor cycling and positioning of signaling molecules. The dynamics of the shape, number, and molecular composition of spines, and how they are regulated by neural activity, are critically important in synaptic efficacy, synaptic plasticity, and ultimately learning and memory. Dendritic spines originate as outward protrusions of the cell membrane, but this aspect of spine formation and stabilization has not been a major focus of investigation compared to studies of membrane protrusions in non-neuronal cells. We review here one family of proteins involved in membrane curvature at synapses, the BAR (Bin-Amphiphysin-Rvs) domain proteins. The subfamily of inverse BAR (I-BAR) proteins sense and introduce outward membrane curvature, and serve as bridges between the cell membrane and the cytoskeleton. We focus on three I-BAR domain proteins that are expressed in the central nervous system: Mtss2, MIM, and IRSp53 that promote negative, concave curvature based on their ability to self-associate. Recent studies suggest that each has distinct functions in synapse formation and synaptic plasticity. The action of I-BARs is also shaped by crosstalk with other signaling components, forming signaling platforms that can function in a circuit-dependent manner. We discuss another potentially important feature-the ability of some BAR domain proteins to impact the function of other family members by heterooligomerization. Understanding the spatiotemporal resolution of synaptic I-BAR protein expression and their interactions should provide insights into the interplay between activity-dependent neural plasticity and network rewiring in the CNS.
Topics: Cell Membrane; Dendritic Spines; Learning; Neuronal Plasticity; Signal Transduction; Synapses
PubMed: 34975417
DOI: 10.3389/fncir.2021.787436 -
Current Opinion in Neurobiology Aug 2020The synaptotagmin family of molecules is known for regulating calcium-dependent membrane fusion events. Mice and humans express 17 synaptotagmin isoforms, where most... (Review)
Review
The synaptotagmin family of molecules is known for regulating calcium-dependent membrane fusion events. Mice and humans express 17 synaptotagmin isoforms, where most studies have focused on isoforms 1, 2, and 7, which are involved in synaptic vesicle exocytosis. Recent work has highlighted how brain function relies on additional isoforms, with roles in postsynaptic receptor endocytosis, vesicle trafficking, membrane repair, synaptic plasticity, and protection against neurodegeneration, for example, in addition to the traditional concept of synaptotagmin-mediated neurotransmitter release - in neurons as well as glia, and at different timepoints. In fact, it is not uncommon for the same isoform to feature several splice isoforms, form homo- and heterodimers, and function in different subcellular locations and cell types. This review aims to highlight the diversity of synaptotagmins, offers a concise summary of key findings on all isoforms, and discusses different ways of grouping these.
Topics: Animals; Calcium; Exocytosis; Humans; Membrane Fusion; Mice; Nerve Tissue Proteins; Protein Isoforms; Synaptotagmin I; Synaptotagmins
PubMed: 32663762
DOI: 10.1016/j.conb.2020.04.006 -
Annual Review of Biophysics Feb 2024Dendritic spines are small, bulbous compartments that function as postsynaptic sites and undergo intense biochemical and biophysical activity. The role of the myriad... (Review)
Review
Dendritic spines are small, bulbous compartments that function as postsynaptic sites and undergo intense biochemical and biophysical activity. The role of the myriad signaling pathways that are implicated in synaptic plasticity is well studied. A recent abundance of quantitative experimental data has made the events associated with synaptic plasticity amenable to quantitative biophysical modeling. Spines are also fascinating biophysical computational units because spine geometry, signal transduction, and mechanics work in a complex feedback loop to tune synaptic plasticity. In this sense, ideas from modeling cell motility can inspire us to develop multiscale approaches for predictive modeling of synaptic plasticity. In this article, we review the key steps in postsynaptic plasticity with a specific focus on the impact of spine geometry on signaling, cytoskeleton rearrangement, and membrane mechanics. We summarize the main experimental observations and highlight how theory and computation can aid our understanding of these complex processes.Expected final online publication date for the , Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
PubMed: 38382115
DOI: 10.1146/annurev-biophys-072123-124954 -
International Journal of Molecular... Dec 2023Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory... (Review)
Review
Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory synaptic transmission in glutamatergic neurons. The number and subunit composition of AMPARs are fundamental to synaptic plasticity and the formation of entire neural networks. Accordingly, the insertion and functionalization of AMPARs at the postsynaptic membrane have become a core issue related to neural circuit formation and information processing in the central nervous system. In this review, we summarize current knowledge regarding the related mechanisms of AMPAR expression and trafficking. The proteins related to AMPAR trafficking are discussed in detail, including vesicle-related proteins, cytoskeletal proteins, synaptic proteins, and protein kinases. Furthermore, significant emphasis was placed on the pivotal role of the actin cytoskeleton, which spans throughout the entire transport process in AMPAR transport, indicating that the actin cytoskeleton may serve as a fundamental basis for AMPAR trafficking. Additionally, we summarize the proteases involved in AMPAR post-translational modifications. Moreover, we provide an overview of AMPAR transport and localization to the postsynaptic membrane. Understanding the assembly, trafficking, and dynamic synaptic expression mechanisms of AMPAR may provide valuable insights into the cognitive decline associated with neurodegenerative diseases.
Topics: Receptors, AMPA; Central Nervous System; Neurons; Cognition; Learning; Central Nervous System Depressants
PubMed: 38203282
DOI: 10.3390/ijms25010111