Journal articles: 'Synaptic adhesion proteins'

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Leshchyns’ka, Iryna, and Vladimir Sytnyk. "Synaptic Cell Adhesion Molecules in Alzheimer’s Disease." Neural Plasticity 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/6427537.

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Alzheimer’s disease (AD) is a neurodegenerative brain disorder associated with the loss of synapses between neurons in the brain. Synaptic cell adhesion molecules are cell surface glycoproteins which are expressed at the synaptic plasma membranes of neurons. These proteins play key roles in formation and maintenance of synapses and regulation of synaptic plasticity. Genetic studies and biochemical analysis of the human brain tissue, cerebrospinal fluid, and sera from AD patients indicate that levels and function of synaptic cell adhesion molecules are affected in AD. Synaptic cell adhesion molecules interact with Aβ, a peptide accumulating in AD brains, which affects their expression and synaptic localization. Synaptic cell adhesion molecules also regulate the production of Aβvia interaction with the key enzymes involved in Aβformation. Aβ-dependent changes in synaptic adhesion affect the function and integrity of synapses suggesting that alterations in synaptic adhesion play key roles in the disruption of neuronal networks in AD.

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Zobel, K., S. E. Choi, R. Minakova, M. Gocyla, and A. Offenhäusser. "N-Cadherin modified lipid bilayers promote neural network formation and circuitry." Soft Matter 13, no. 44 (2017): 8096–107. http://dx.doi.org/10.1039/c7sm01214d.

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Hayano, Yasufumi, Yugo Ishino, Jung Ho Hyun, Carlos G. Orozco, André Steinecke, Elizabeth Potts, Yasuhiro Oisi, et al. "IgSF11 homophilic adhesion proteins promote layer-specific synaptic assembly of the cortical interneuron subtype." Science Advances 7, no. 29 (July 2021): eabf1600. http://dx.doi.org/10.1126/sciadv.abf1600.

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The most prominent structural hallmark of the mammalian neocortical circuitry is the layer-based organization of specific cell types and synaptic inputs. Accordingly, cortical inhibitory interneurons (INs), which shape local network activity, exhibit subtype-specific laminar specificity of synaptic outputs. However, the underlying molecular mechanisms remain unknown. Here, we demonstrate that Immunoglobulin Superfamily member 11 (IgSF11) homophilic adhesion proteins are preferentially expressed in one of the most distinctive IN subtypes, namely, chandelier cells (ChCs) that specifically innervate axon initial segments of pyramidal neurons (PNs), and their synaptic laminar target. Loss-of-function experiments in either ChCs or postsynaptic cells revealed that IgSF11 is required for ChC synaptic development in the target layer. While overexpression of IgSF11 in ChCs enlarges ChC presynaptic boutons, expressing IgSF11 in nontarget layers induces ectopic ChC synapses. These findings provide evidence that synapse-promoting adhesion proteins, highly localized to synaptic partners, determine the layer-specific synaptic connectivity of the cortical IN subtype.

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Brose, N. "Neuroligin-family synaptic adhesion proteins in autism spectrum disorders." European Neuropsychopharmacology 26 (October 2016): S131. http://dx.doi.org/10.1016/s0924-977x(16)30913-0.

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Stewart, Luke T. "Cell adhesion proteins and the pathogenesis of autism spectrum disorders." Journal of Neurophysiology 113, no. 5 (March 1, 2015): 1283–86. http://dx.doi.org/10.1152/jn.00780.2013.

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Current theories on the pathogenesis of autism spectrum disorders (ASD) maintain that the associated cognitive and behavioral symptoms are caused by aberrant synaptic transmission affecting specific brain circuits. Transgenic mouse models have implicated the involvement of cell adhesion proteins in synaptic dysfunction and ASD pathogenesis. Recently, Aoto et al. ( Cell 154: 75–88, 2013) has shown that alternatively spliced neurexin proteins affect the efficacy of AMPA receptor-mediated excitatory currents in both cultured neuronal networks and acute hippocampal slices constituting a potential ASD-related electrophysiological phenotype.

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Lee, Tet Woo, Vicky W. K. Tsang, and Nigel P. Birch. "Synaptic plasticity-associated proteases and protease inhibitors in the brain linked to the processing of extracellular matrix and cell adhesion molecules." Neuron Glia Biology 4, no. 3 (August 2008): 223–34. http://dx.doi.org/10.1017/s1740925x09990172.

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Research on the molecular and cellular basis of learning and memory has focused on the mechanisms that underlie the induction and expression of synaptic plasticity. There is increasing evidence that structural changes at the synapse are associated with synaptic plasticity and that extracellular matrix (ECM) components and cell adhesion molecules are associated with these changes. The functions of both groups of molecules can be regulated by proteolysis. In this article we review the roles of selected proteases and protease inhibitors in perisynaptic proteolysis of the ECM and synaptic adhesion proteins and the impact of proteolysis on synaptic modification and cognitive function.

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Uchida, N., Y. Honjo, K. R. Johnson, M. J. Wheelock, and M. Takeichi. "The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones." Journal of Cell Biology 135, no. 3 (November 1, 1996): 767–79. http://dx.doi.org/10.1083/jcb.135.3.767.

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Molecular mechanisms linking pre- and postsynaptic membranes at the interneuronal synapses are little known. We tested the cadherin adhesion system for its localization in synapses of mouse and chick brains. We found that two classes of cadherin-associated proteins, alpha N- and beta-catenin, are broadly distributed in adult brains, colocalizing with a synaptic marker, synaptophysin. At the ultrastructural level, these proteins were localized in synaptic junctions of various types, forming a symmetrical adhesion structure. These structures sharply bordered the transmitter release sites associated with synaptic vesicles, although their segregation was less clear in certain types of synapses. N-cadherin was also localized at a similar site of synaptic junctions but in restricted brain nuclei. In developing synapses, the catenin-bearing contacts dominated their junctional structures. These findings demonstrate that interneuronal synaptic junctions comprise two subdomains, transmitter release zone and catenin-based adherens junction. The catenins localized in these junctions are likely associated with certain cadherin molecules including N-cadherin, and the cadherin/ catenin complex may play a critical role in the formation or maintenance of synaptic junctions.

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Olsen, Olav, Kimberly A. Moore, Masaki Fukata, Toshinari Kazuta, Jonathan C. Trinidad, Fred W. Kauer, Michel Streuli, et al. "Neurotransmitter release regulated by a MALS–liprin-α presynaptic complex." Journal of Cell Biology 170, no. 7 (September 26, 2005): 1127–34. http://dx.doi.org/10.1083/jcb.200503011.

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Synapses are highly specialized intercellular junctions organized by adhesive and scaffolding molecules that align presynaptic vesicular release with postsynaptic neurotransmitter receptors. The MALS/Veli–CASK–Mint-1 complex of PDZ proteins occurs on both sides of the synapse and has the potential to link transsynaptic adhesion molecules to the cytoskeleton. In this study, we purified the MALS protein complex from brain and found liprin-α as a major component. Liprin proteins organize the presynaptic active zone and regulate neurotransmitter release. Fittingly, mutant mice lacking all three MALS isoforms died perinatally with difficulty breathing and impaired excitatory synaptic transmission. Excitatory postsynaptic currents were dramatically reduced in autaptic cultures from MALS triple knockout mice due to a presynaptic deficit in vesicle cycling. These findings are consistent with a model whereby the MALS–CASK–liprin-α complex recruits components of the synaptic release machinery to adhesive proteins of the active zone.

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Costain, Willard J., Ingrid Rasquinha, Jagdeep K. Sandhu, Peter Rippstein, Bogdan Zurakowski, Jacqueline Slinn, John P. MacManus, and Danica B. Stanimirovic. "Cerebral Ischemia Causes Dysregulation of Synaptic Adhesion in Mouse Synaptosomes." Journal of Cerebral Blood Flow & Metabolism 28, no. 1 (May 16, 2007): 99–110. http://dx.doi.org/10.1038/sj.jcbfm.9600510.

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Synaptic pathology is observed during hypoxic events in the central nervous system in the form of altered dendrite structure and conductance changes. These alterations are rapidly reversible, on the return of normoxia, but are thought to initiate subsequent neuronal cell death. To characterize the effects of hypoxia on regulators of synaptic stability, we examined the temporal expression of cell adhesion molecules (CAMs) in synaptosomes after transient middle cerebral artery occlusion (MCAO) in mice. We focused on events preceding the onset of ischemic neuronal cell death (< 48 h). Synaptosome preparations were enriched in synaptically localized proteins and were free of endoplasmic reticulum and nuclear contamination. Electron microscopy showed that the synaptosome preparation was enriched in spheres (≈650 nm in diameter) containing secretory vesicles and postsynaptic densities. Forebrain mRNA levels of synaptically located CAMs was unaffected at 3 h after MCAO. This is contrasted by the observation of consistent downregulation of synaptic CAMs at 20 h after MCAO. Examination of synaptosomal CAM protein content indicated that certain adhesion molecules were decreased as early as 3 h after MCAO. For comparison, synaptosomal Agrn protein levels were unaffected by cerebral ischemia. Furthermore, a marked increase in the levels of p-Ctnnb1 in ischemic synaptosomes was observed. p-Ctnnb1 was detected in hippocampal fiber tracts and in cornu ammonis 1 neuronal nuclei. These results indicate that ischemia induces a dysregulation of a subset of synaptic proteins that are important regulators of synaptic plasticity before the onset of ischemic neuronal cell death.

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Ribic, Adema, and Thomas Biederer. "Emerging Roles of Synapse Organizers in the Regulation of Critical Periods." Neural Plasticity 2019 (September 3, 2019): 1–9. http://dx.doi.org/10.1155/2019/1538137.

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Experience remodels cortical connectivity during developmental windows called critical periods. Experience-dependent regulation of synaptic strength during these periods establishes circuit functions that are stabilized as critical period plasticity wanes. These processes have been extensively studied in the developing visual cortex, where critical period opening and closure are orchestrated by the assembly, maturation, and strengthening of distinct synapse types. The synaptic specificity of these processes points towards the involvement of distinct molecular pathways. Attractive candidates are pre- and postsynaptic transmembrane proteins that form adhesive complexes across the synaptic cleft. These synapse-organizing proteins control synapse development and maintenance and modulate structural and functional properties of synapses. Recent evidence suggests that they have pivotal roles in the onset and closure of the critical period for vision. In this review, we describe roles of synapse-organizing adhesion molecules in the regulation of visual critical period plasticity and we discuss the potential they offer to restore circuit functions in amblyopia and other neurodevelopmental disorders.

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Kohsaka, Hiroshi, Etsuko Takasu, and Akinao Nose. "In vivo induction of postsynaptic molecular assembly by the cell adhesion molecule Fasciclin2." Journal of Cell Biology 179, no. 6 (December 10, 2007): 1289–300. http://dx.doi.org/10.1083/jcb.200705154.

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Cell adhesion molecules (CAMs) are thought to mediate interactions between innervating axons and their targets. However, such interactions have not been directly observed in vivo. In this paper, we study the function and dynamics of Fasciclin2 (Fas2), a homophilic CAM expressed both pre- and postsynaptically during neuromuscular synapse formation in Drosophila melanogaster. We apply live imaging of functional fluorescent fusion proteins expressed in muscles and find that Fas2 and Discs-Large (Dlg; a scaffolding protein known to bind Fas2) accumulate at the synaptic contact site soon after the arrival of the nerve. Genetic, deletion, and photobleaching analyses suggest that Fas2-mediated trans-synaptic adhesion is important for the postsynaptic accumulation of both Fas2 itself and Dlg. In fas2 mutants, many aspects of synapse formation appear normal; however, we see a reduction in the synaptic accumulation of Scribble (another scaffolding protein) and glutamate receptor subunits GluRIIA and GluRIIB. We propose that Fas2 mediates trans-synaptic adhesion, which contributes to postsynaptic molecular assembly at the onset of synaptogenesis.

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Smith, Ireland R., Emily L. Hendricks, Nina K. Latcheva, Daniel R. Marenda, and Faith L. W. Liebl. "The CHD Protein Kismet Restricts the Synaptic Localization of Cell Adhesion Molecules at the Drosophila Neuromuscular Junction." International Journal of Molecular Sciences 25, no. 5 (March 6, 2024): 3074. http://dx.doi.org/10.3390/ijms25053074.

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The appropriate expression and localization of cell surface cell adhesion molecules must be tightly regulated for optimal synaptic growth and function. How neuronal plasma membrane proteins, including cell adhesion molecules, cycle between early endosomes and the plasma membrane is poorly understood. Here we show that the Drosophila homolog of the chromatin remodeling enzymes CHD7 and CHD8, Kismet, represses the synaptic levels of several cell adhesion molecules. Neuroligins 1 and 3 and the integrins αPS2 and βPS are increased at kismet mutant synapses but Kismet only directly regulates transcription of neuroligin 2. Kismet may therefore regulate synaptic CAMs indirectly by activating transcription of gene products that promote intracellular vesicle trafficking including endophilin B (endoB) and/or rab11. Knock down of EndoB in all tissues or neurons increases synaptic FasII while knock down of EndoB in kis mutants does not produce an additive increase in FasII. In contrast, neuronal expression of Rab11, which is deficient in kis mutants, leads to a further increase in synaptic FasII in kis mutants. These data support the hypothesis that Kis influences the synaptic localization of FasII by promoting intracellular vesicle trafficking through the early endosome.

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Mah, W., J. Ko, J. Nam, K. Han, W. S. Chung, and E. Kim. "Selected SALM (Synaptic Adhesion-Like Molecule) Family Proteins Regulate Synapse Formation." Journal of Neuroscience 30, no. 16 (April 21, 2010): 5559–68. http://dx.doi.org/10.1523/jneurosci.4839-09.2010.

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Schöpf, Clemens L., Cornelia Ablinger, Stefanie M. Geisler, Ruslan I. Stanika, Marta Campiglio, Walter A. Kaufmann, Benedikt Nimmervoll, et al. "Presynaptic α2δ subunits are key organizers of glutamatergic synapses." Proceedings of the National Academy of Sciences 118, no. 14 (March 29, 2021): e1920827118. http://dx.doi.org/10.1073/pnas.1920827118.

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In nerve cells the genes encoding for α2δ subunits of voltage-gated calcium channels have been linked to synaptic functions and neurological disease. Here we show that α2δ subunits are essential for the formation and organization of glutamatergic synapses. Using a cellular α2δ subunit triple-knockout/knockdown model, we demonstrate a failure in presynaptic differentiation evidenced by defective presynaptic calcium channel clustering and calcium influx, smaller presynaptic active zones, and a strongly reduced accumulation of presynaptic vesicle-associated proteins (synapsin and vGLUT). The presynaptic defect is associated with the downscaling of postsynaptic AMPA receptors and the postsynaptic density. The role of α2δ isoforms as synaptic organizers is highly redundant, as each individual α2δ isoform can rescue presynaptic calcium channel trafficking and expression of synaptic proteins. Moreover, α2δ-2 and α2δ-3 with mutated metal ion-dependent adhesion sites can fully rescue presynaptic synapsin expression but only partially calcium channel trafficking, suggesting that the regulatory role of α2δ subunits is independent from its role as a calcium channel subunit. Our findings influence the current view on excitatory synapse formation. First, our study suggests that postsynaptic differentiation is secondary to presynaptic differentiation. Second, the dependence of presynaptic differentiation on α2δ implicates α2δ subunits as potential nucleation points for the organization of synapses. Finally, our results suggest that α2δ subunits act as transsynaptic organizers of glutamatergic synapses, thereby aligning the synaptic active zone with the postsynaptic density.

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Lin, Bin, Amy C. Arai, Gary Lynch, and Christine M. Gall. "Integrins Regulate NMDA Receptor-Mediated Synaptic Currents." Journal of Neurophysiology 89, no. 5 (May 1, 2003): 2874–78. http://dx.doi.org/10.1152/jn.00783.2002.

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Synapses contain high concentrations of integrins, adhesion receptors known to influence the operation of neighboring transmembrane proteins. Evidence that integrins are important for consolidation of long-term potentiation suggests that these adhesion proteins may modulate activities of synaptic glutamate receptors. The present study provides a first test of the possibility that integrins modulate synaptic N-methyl-d-aspartate (NMDA)-type glutamate receptor activities. Excitatory postsynaptic currents (EPSCs) were recorded with whole cell clamp from hippocampal slices in which AMPA-type glutamate receptors and GABAA receptors were pharmacologically blocked. Microperfusion of the peptide integrin ligand gly-arg-gly-asp-ser-pro (GRGDSP) caused an approximately twofold increase in the amplitude and duration of NMDA receptor-gated synaptic currents. Control peptides had no effect. Paired-pulse facilitation was unchanged, indicating that the ligand did not modify neurotransmitter release probabilities. Infusion of the Src kinase antagonist PP2 but not the control drug 4-amino-7-phenylpyrazolo[3,4-d]pyrimidine eliminated the enhancing effect of GRGDSP. Integrins regulate Src kinases that are known to phosphorylate NMDA receptors. It is concluded that integrins act through this route to exert potent modulatory effects on the operation of NMDA receptors.

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Boll, Inga, Pia Jensen, Veit Schwämmle, and Martin R. Larsen. "Depolarization-dependent Induction of Site-specific Changes in Sialylation on N-linked Glycoproteins in Rat Nerve Terminals." Molecular & Cellular Proteomics 19, no. 9 (June 9, 2020): 1418–35. http://dx.doi.org/10.1074/mcp.ra119.001896.

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Synaptic transmission leading to release of neurotransmitters in the nervous system is a fast and highly dynamic process. Previously, protein interaction and phosphorylation have been thought to be the main regulators of synaptic transmission. Here we show that sialylation of N-linked glycosylation is a novel potential modulator of neurotransmitter release mechanisms by investigating depolarization-dependent changes of formerly sialylated N-linked glycopeptides. We suggest that negatively charged sialic acids can be modulated, similarly to phosphorylation, by the action of sialyltransferases and sialidases thereby changing local structure and function of membrane glycoproteins. We characterized site-specific alteration in sialylation on N-linked glycoproteins in isolated rat nerve terminals after brief depolarization using quantitative sialiomics. We identified 1965 formerly sialylated N-linked glycosites in synaptic proteins and found that the abundances of 430 glycosites changed after 5 s depolarization. We observed changes on essential synaptic proteins such as synaptic vesicle proteins, ion channels and transporters, neurotransmitter receptors and cell adhesion molecules. This study is to our knowledge the first to describe ultra-fast site-specific modulation of the sialiome after brief stimulation of a biological system.

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Chamma, Ingrid, Florian Levet, Jean-Baptiste Sibarita, Matthieu Sainlos, and Olivier Thoumine. "Nanoscale organization of synaptic adhesion proteins revealed by single-molecule localization microscopy." Neurophotonics 3, no. 4 (November 3, 2016): 041810. http://dx.doi.org/10.1117/1.nph.3.4.041810.

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Honer, W. G., P. Falkai, C. Young, T. Wang, J. Xie, J. Bonner, L. Hu, G. L. Boulianne, Z. Luo, and W. S. Trimble. "Cingulate cortex synaptic terminal proteins and neural cell adhesion molecule in schizophrenia." Neuroscience 78, no. 1 (February 1997): 99–110. http://dx.doi.org/10.1016/s0306-4522(96)00489-7.

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Brose, N. "Synaptic Cell Adhesion Proteins and Synaptogenesis in the Mammalian Central Nervous System." Naturwissenschaften 86, no. 11 (November 3, 1999): 516–24. http://dx.doi.org/10.1007/s001140050666.

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Torres, Viviana I., Daniela Vallejo, and Nibaldo C. Inestrosa. "Emerging Synaptic Molecules as Candidates in the Etiology of Neurological Disorders." Neural Plasticity 2017 (2017): 1–25. http://dx.doi.org/10.1155/2017/8081758.

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Synapses are complex structures that allow communication between neurons in the central nervous system. Studies conducted in vertebrate and invertebrate models have contributed to the knowledge of the function of synaptic proteins. The functional synapse requires numerous protein complexes with specialized functions that are regulated in space and time to allow synaptic plasticity. However, their interplay during neuronal development, learning, and memory is poorly understood. Accumulating evidence links synapse proteins to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. In this review, we describe the way in which several proteins that participate in cell adhesion, scaffolding, exocytosis, and neurotransmitter reception from presynaptic and postsynaptic compartments, mainly from excitatory synapses, have been associated with several synaptopathies, and we relate their functions to the disease phenotype.

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Stachowicz, Katarzyna. "Physicochemical Principles of Adhesion Mechanisms in the Brain." International Journal of Molecular Sciences 24, no. 6 (March 7, 2023): 5070. http://dx.doi.org/10.3390/ijms24065070.

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The brain functions through neuronal circuits and networks that are synaptically connected. This type of connection can exist due to physical forces that interact to stabilize local contacts in the brain. Adhesion is a fundamental physical phenomenon that allows different layers, phases, and tissues to connect. Similarly, synaptic connections are stabilized by specialized adhesion proteins. This review discusses the basic physical and chemical properties of adhesion. Cell adhesion molecules (CAMs) such as cadherins, integrins, selectins, and immunoglobulin family of cell adhesion molecules (IgSF) will be discussed, and their role in physiological and pathological brain function. Finally, the role of CAMs at the synapse will be described. In addition, methods for studying adhesion in the brain will be presented.

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Bhouri, Mehdi, Wade Morishita, Paul Temkin, Debanjan Goswami, Hiroshi Kawabe, Nils Brose, Thomas C. Südhof, Ann Marie Craig, Tabrez J. Siddiqui, and Robert Malenka. "Deletion of LRRTM1 and LRRTM2 in adult mice impairs basal AMPA receptor transmission and LTP in hippocampal CA1 pyramidal neurons." Proceedings of the National Academy of Sciences 115, no. 23 (May 21, 2018): E5382—E5389. http://dx.doi.org/10.1073/pnas.1803280115.

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Leucine-rich repeat transmembrane (LRRTM) proteins are synaptic cell adhesion molecules that influence synapse formation and function. They are genetically associated with neuropsychiatric disorders, and via their synaptic actions likely regulate the establishment and function of neural circuits in the mammalian brain. Here, we take advantage of the generation of a LRRTM1 and LRRTM2 double conditional knockout mouse (LRRTM1,2 cKO) to examine the role of LRRTM1,2 at mature excitatory synapses in hippocampal CA1 pyramidal neurons. Genetic deletion of LRRTM1,2 in vivo in CA1 neurons using Cre recombinase-expressing lentiviruses dramatically impaired long-term potentiation (LTP), an impairment that was rescued by simultaneous expression of LRRTM2, but not LRRTM4. Mutation or deletion of the intracellular tail of LRRTM2 did not affect its ability to rescue LTP, while point mutations designed to impair its binding to presynaptic neurexins prevented rescue of LTP. In contrast to previous work using shRNA-mediated knockdown of LRRTM1,2, KO of these proteins at mature synapses also caused a decrease in AMPA receptor-mediated, but not NMDA receptor-mediated, synaptic transmission and had no detectable effect on presynaptic function. Imaging of recombinant photoactivatable AMPA receptor subunit GluA1 in the dendritic spines of cultured neurons revealed that it was less stable in the absence of LRRTM1,2. These results illustrate the advantages of conditional genetic deletion experiments for elucidating the function of endogenous synaptic proteins and suggest that LRRTM1,2 proteins help stabilize synaptic AMPA receptors at mature spines during basal synaptic transmission and LTP.

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Mitoma, Hiroshi, Jerome Honnorat, Kazuhiko Yamaguchi, and Mario Manto. "Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias." International Journal of Molecular Sciences 21, no. 14 (July 13, 2020): 4936. http://dx.doi.org/10.3390/ijms21144936.

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In the last years, different kinds of limbic encephalitis associated with autoantibodies against ion channels and synaptic receptors have been described. Many studies have demonstrated that such autoantibodies induce channel or receptor dysfunction. The same mechanism is discussed in immune-mediated cerebellar ataxias (IMCAs), but the pathogenesis has been less investigated. The aim of the present review is to evaluate what kind of cerebellar ion channels, their related proteins, and the synaptic machinery proteins that are preferably impaired by autoantibodies so as to develop cerebellar ataxias (CAs). The cerebellum predictively coordinates motor and cognitive functions through a continuous update of an internal model. These controls are relayed by cerebellum-specific functions such as precise neuronal discharges with potassium channels, synaptic plasticity through calcium signaling pathways coupled with voltage-gated calcium channels (VGCC) and metabotropic glutamate receptors 1 (mGluR1), a synaptic organization with glutamate receptor delta (GluRδ), and output signal formation through chained GABAergic neurons. Consistently, the association of CAs with anti-potassium channel-related proteins, anti-VGCC, anti-mGluR1, and GluRδ, and anti-glutamate decarboxylase 65 antibodies is observed in IMCAs. Despite ample distributions of AMPA and GABA receptors, however, CAs are rare in conditions with autoantibodies against these receptors. Notably, when the autoantibodies impair synaptic transmission, the autoimmune targets are commonly classified into three categories: release machinery proteins, synaptic adhesion molecules, and receptors. This physiopathological categorization impacts on both our understanding of the pathophysiology and clinical prognosis.

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Pehkonen, Henna, Ivan de Curtis, and Outi Monni. "Liprins in oncogenic signaling and cancer cell adhesion." Oncogene 40, no. 46 (October 15, 2021): 6406–16. http://dx.doi.org/10.1038/s41388-021-02048-1.

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AbstractLiprins are a multifunctional family of scaffold proteins, identified by their involvement in several important neuronal functions related to signaling and organization of synaptic structures. More recently, the knowledge on the liprin family has expanded from neuronal functions to processes relevant to cancer progression, including cell adhesion, cell motility, cancer cell invasion, and signaling. These proteins consist of regions, which by prediction are intrinsically disordered, and may be involved in the assembly of supramolecular structures relevant for their functions. This review summarizes the current understanding of the functions of liprins in different cellular processes, with special emphasis on liprins in tumor progression. The available data indicate that liprins may be potential biomarkers for cancer progression and may have therapeutic importance.

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Sandau, Ursula S., Alison E. Mungenast, Jack McCarthy, Thomas Biederer, Gabriel Corfas, and Sergio R. Ojeda. "The Synaptic Cell Adhesion Molecule, SynCAM1, Mediates Astrocyte-to-Astrocyte and Astrocyte-to-GnRH Neuron Adhesiveness in the Mouse Hypothalamus." Endocrinology 152, no. 6 (April 12, 2011): 2353–63. http://dx.doi.org/10.1210/en.2010-1434.

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We previously identified synaptic cell adhesion molecule 1 (SynCAM1) as a component of a genetic network involved in the hypothalamic control of female puberty. Although it is well established that SynCAM1 is a synaptic adhesion molecule, its contribution to hypothalamic function is unknown. Here we show that, in addition to the expected neuronal localization illustrated by its presence in GnRH neurons, SynCAM1 is expressed in hypothalamic astrocytes. Cell adhesion assays indicated that SynCAM is recognized by both GnRH neurons and astrocytes as an adhesive partner and promotes cell-cell adhesiveness via homophilic, extracellular domain-mediated interactions. Alternative splicing of the SynCAM1 primary mRNA transcript yields four mRNAs encoding membrane-spanning SynCAM1 isoforms. Variants 1 and 4 are predicted to be both N and O glycosylated. Hypothalamic astrocytes and GnRH-producing GT1-7 cells express mainly isoform 4 mRNA, and sequential N- and O-deglycosylation of proteins extracted from these cells yields progressively smaller SynCAM1 species, indicating that isoform 4 is the predominant SynCAM1 variant expressed in astrocytes and GT1-7 cells. Neither cell type expresses the products of two other SynCAM genes (SynCAM2 and SynCAM3), suggesting that SynCAM-mediated astrocyte-astrocyte and astrocyte-GnRH neuron adhesiveness is mostly mediated by SynCAM1 homophilic interactions. When erbB4 receptor function is disrupted in astrocytes, via transgenic expression of a dominant-negative erbB4 receptor form, SynCAM1-mediated adhesiveness is severely compromised. Conversely, SynCAM1 adhesive behavior is rapidly, but transiently, enhanced in astrocytes by ligand-dependent activation of erbB4 receptors, suggesting that erbB4-mediated events affecting SynCAM1 function contribute to regulate astrocyte adhesive communication.

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Cijsouw, Tony, Austin Ramsey, TuKiet Lam, Beatrice Carbone, Thomas Blanpied, and Thomas Biederer. "Mapping the Proteome of the Synaptic Cleft through Proximity Labeling Reveals New Cleft Proteins." Proteomes 6, no. 4 (November 28, 2018): 48. http://dx.doi.org/10.3390/proteomes6040048.

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Synapses are specialized neuronal cell-cell contacts that underlie network communication in the mammalian brain. Across neuronal populations and circuits, a diverse set of synapses is utilized, and they differ in their molecular composition to enable heterogenous connectivity patterns and functions. In addition to pre- and post-synaptic specializations, the synaptic cleft is now understood to be an integral compartment of synapses that contributes to their structural and functional organization. Aiming to map the cleft proteome, this study applied a peroxidase-mediated proximity labeling approach and used the excitatory synaptic cell adhesion protein SynCAM 1 fused to horseradish peroxidase (HRP) as a reporter in cultured cortical neurons. This reporter marked excitatory synapses as measured by confocal microcopy and was targeted to the edge zone of the synaptic cleft as determined using 3D dSTORM super-resolution imaging. Proximity labeling with a membrane-impermeant biotin-phenol compound restricted labeling to the cell surface, and Label-Free Quantitation (LFQ) mass spectrometry combined with ratiometric HRP tagging of membrane vs. synaptic surface proteins was used to identify the proteomic content of excitatory clefts. Novel cleft candidates were identified, and Receptor-type tyrosine-protein phosphatase zeta was selected and successfully validated. This study supports the robust applicability of peroxidase-mediated proximity labeling for synaptic cleft proteomics and its potential for understanding synapse heterogeneity in health and changes in diseases such as psychiatric disorders and addiction.

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Hu, Xiaoge, Jian-hong Luo, and Junyu Xu. "The Interplay between Synaptic Activity and Neuroligin Function in the CNS." BioMed Research International 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/498957.

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Neuroligins (NLs) are postsynaptic transmembrane cell-adhesion proteins that play a key role in the regulation of excitatory and inhibitory synapses. Previousin vitroandin vivostudies have suggested that NLs contribute to synapse formation and synaptic transmission. Consistent with their localization, NL1 and NL3 selectively affect excitatory synapses, whereas NL2 specifically affects inhibitory synapses. Deletions or mutations in NL genes have been found in patients with autism spectrum disorders or mental retardations, and mice harboring the reported NL deletions or mutations exhibit autism-related behaviors and synapse dysfunction. Conversely, synaptic activity can regulate the phosphorylation, expression, and cleavage of NLs, which, in turn, can influence synaptic activity. Thus, in clinical research, identifying the relationship between NLs and synapse function is critical. In this review, we primarily discuss how NLs and synaptic activity influence each other.

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Ramsey, Austin M., Ai-Hui Tang, Tara A. LeGates, Xu-Zhuo Gou, Beatrice E. Carbone, Scott M. Thompson, Thomas Biederer, and Thomas A. Blanpied. "Subsynaptic positioning of AMPARs by LRRTM2 controls synaptic strength." Science Advances 7, no. 34 (August 2021): eabf3126. http://dx.doi.org/10.1126/sciadv.abf3126.

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Recent evidence suggests that nano-organization of proteins within synapses may control the strength of communication between neurons in the brain. The unique subsynaptic distribution of glutamate receptors, which cluster in nanoalignment with presynaptic sites of glutamate release, supports this hypothesis. However, testing it has been difficult because mechanisms controlling subsynaptic organization remain unknown. Reasoning that transcellular interactions could position AMPA receptors (AMPARs), we targeted a key transsynaptic adhesion molecule implicated in controlling AMPAR number, LRRTM2, using engineered, rapid proteolysis. Severing the LRRTM2 extracellular domain led quickly to nanoscale declustering of AMPARs away from release sites, not prompting their escape from synapses until much later. This rapid remodeling of AMPAR position produced significant deficits in evoked, but not spontaneous, postsynaptic receptor activation. These results dissociate receptor numbers from their nanopositioning in determination of synaptic function and support the novel concept that adhesion molecules acutely position receptors to dynamically control synaptic strength.

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Lu, Cecilia S., Bo Zhai, Alex Mauss, Matthias Landgraf, Stephen Gygi, and David Van Vactor. "MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development." Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1652 (September 26, 2014): 20130517. http://dx.doi.org/10.1098/rstb.2013.0517.

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Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila . However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins.

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Zambonino, Marjorie, and Pamela Pereira. "The structure of Neurexin 1α (n1α) and its role as synaptic organizer." Bionatura 4, no. 2 (May 15, 2019): 883–86. http://dx.doi.org/10.21931/rb/2019.04.02.12.

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α - and b-neurexins (NRXNs) are transmembrane adhesion protein complexes localized in presynaptic membranes into neurons and interact with the postsynaptic neuroligins (NLGNs). Our findings indicate that the neurexin 1α (n1α) is a synaptic organizer that directs postsynaptic development in neurons, evidenced in GABAergic neurons and trials with Knock-out Mice. Also, the interactions between hypervariable surfaces of n1α and ligands (neurexophilin, a-dystroglycan, and GABAA) promotes a proper protein-binding recognition, and consequently, a better synaptic adhesion. There is a direct relationship between mental disorders and the n1α assemblage because NRXN1 gene encodes for n1α proteins which are involved in the transmission of information into the brain. For this reason, damage in this complex-protein or some neurexin gene variations causes pathological abnormalities and neuropsychiatric diseases such as schizophrenia, autism spectrum disorders, and intellectual disabilities.

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Kreienkamp, H. J., M. Soltau, D. Richter, and T. Böckers. "Interaction of G-protein-coupled receptors with synaptic scaffolding proteins." Biochemical Society Transactions 30, no. 4 (August 1, 2002): 464–68. http://dx.doi.org/10.1042/bst0300464.

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The calcium-independent receptors for latrotoxin (CIRL1-CIRL3) constitute a family of seven-transmembrane receptors with an unsually large N-terminal extracellular domain which comprises several motifs usually found in cell adhesion molecules. By yeast two-hybrid screening, we have identified the intracellular C-termini of CIRL1 and CIRL2 as interaction partners of the PDZ domain of the proline-rich synapse-associated protein (ProSAP)/somatostatin receptor-interacting protein (SSTRIP) family of postsynaptic proteins (SSTRIP, ProSAP1 and ProSAP2, also known as shank1-shank3 respectively). Overlay assays indicate that the ProSAP1/shank2 PDZ domain in particular interacts strongly with the C-terminus of CIRL1 and CIRL2. Co-immuno-precipitation of ProSAP1 and CIRL1 (but not CIRL2) from rat brain extracts indicates that this interaction also occurs in vivo in rat brain. The known postsynaptic localization of ProSAP1, as well as our observation that CIRL1 (but not CIRL2) is enriched in postsynaptic density preparations from the rat brain, suggests that CIRL1 is localized pre- as well as post-synaptically in the central nervous system.

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Goethe, Eric A., Benjamin Deneen, Jeffrey Noebels, and Ganesh Rao. "The Role of Hyperexcitability in Gliomagenesis." International Journal of Molecular Sciences 24, no. 1 (January 1, 2023): 749. http://dx.doi.org/10.3390/ijms24010749.

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Glioblastoma is the most common malignant primary brain tumor. Recent studies have demonstrated that excitatory or activity-dependent signaling—both synaptic and non-synaptic—contribute to the progression of glioblastoma. Glutamatergic receptors may be stimulated via neuron–tumor synapses or release of glutamate by the tumor itself. Ion currents generated by these receptors directly alter the structure of membrane adhesion molecules and cytoskeletal proteins to promote migratory behavior. Additionally, the hyperexcitable milieu surrounding glioma increases the rate at which tumor cells proliferate and drive recurrent disease. Inhibition of excitatory signaling has shown to effectively reduce its pro-migratory and -proliferative effects.

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Kuhl, D., T. E. Kennedy, A. Barzilai, and E. R. Kandel. "Long-term sensitization training in Aplysia leads to an increase in the expression of BiP, the major protein chaperon of the ER." Journal of Cell Biology 119, no. 5 (December 1, 1992): 1069–76. http://dx.doi.org/10.1083/jcb.119.5.1069.

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Long-term memory for sensitization of the gill- and siphon-withdrawal reflexes in Aplysia californica requires RNA and protein synthesis. These long-term behavioral changes are accompanied by long-term facilitation of the synaptic connections between the gill and siphon sensory and motor neurons, which are similarly dependent on transcription and translation. In addition to showing an increase in over-all protein synthesis, long-term facilitation is associated with changes in the expression of specific early, intermediate, and late proteins, and with the growth of new synaptic connections between the sensory and motor neurons of the reflex. We previously focused on early proteins and have identified four proteins as members of the immunoglobulin family of cell adhesion molecules related to NCAM and fasciclin II. We have now cloned the cDNA corresponding to one of the late proteins, and identified it as the Aplysia homolog of BiP, an ER resident protein involved in the folding and assembly of secretory and membrane proteins. Behavioral training increases the steady-state level of BiP mRNA in the sensory neurons. The increase in the synthesis of BiP protein is first detected 3 h after the onset of facilitation, when the increase in overall protein synthesis reaches its peak and the formation of new synaptic terminals becomes apparent. These findings suggest that the chaperon function of BiP might serve to fold proteins and assemble protein complexes necessary for the structural changes characteristic of long-term memory.

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Loomis, Connor, Aliyah Stephens, Remi Janicot, Usman Baqai, Laura Drebushenko, and Jennifer Round. "Identification of MAGUK scaffold proteins as intracellular binding partners of synaptic adhesion protein Slitrk2." Molecular and Cellular Neuroscience 103 (March 2020): 103465. http://dx.doi.org/10.1016/j.mcn.2019.103465.

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Figiel, Izabela, Patrycja K. Kruk, Monika Zaręba-Kozioł, Paulina Rybak, Monika Bijata, Jakub Wlodarczyk, and Joanna Dzwonek. "MMP-9 Signaling Pathways That Engage Rho GTPases in Brain Plasticity." Cells 10, no. 1 (January 15, 2021): 166. http://dx.doi.org/10.3390/cells10010166.

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The extracellular matrix (ECM) has been identified as a critical factor affecting synaptic function. It forms a functional scaffold that provides both the structural support and the reservoir of signaling molecules necessary for communication between cellular constituents of the central nervous system (CNS). Among numerous ECM components and modifiers that play a role in the physiological and pathological synaptic plasticity, matrix metalloproteinase 9 (MMP-9) has recently emerged as a key molecule. MMP-9 may contribute to the dynamic remodeling of structural and functional plasticity by cleaving ECM components and cell adhesion molecules. Notably, MMP-9 signaling was shown to be indispensable for long-term memory formation that requires synaptic remodeling. The core regulators of the dynamic reorganization of the actin cytoskeleton and cell adhesion are the Rho family of GTPases. These proteins have been implicated in the control of a wide range of cellular processes occurring in brain physiology and pathology. Here, we discuss the contribution of Rho GTPases to MMP-9-dependent signaling pathways in the brain. We also describe how the regulation of Rho GTPases by post-translational modifications (PTMs) can influence these processes.

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Yang, Xiaojuan, and Wim Annaert. "The Nanoscopic Organization of Synapse Structures: A Common Basis for Cell Communication." Membranes 11, no. 4 (March 30, 2021): 248. http://dx.doi.org/10.3390/membranes11040248.

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Synapse structures, including neuronal and immunological synapses, can be seen as the plasma membrane contact sites between two individual cells where information is transmitted from one cell to the other. The distance between the two plasma membranes is only a few tens of nanometers, but these areas are densely populated with functionally different proteins, including adhesion proteins, receptors, and transporters. The narrow space between the two plasma membranes has been a barrier for resolving the synaptic architecture due to the diffraction limit in conventional microscopy (~250 nm). Various advanced super-resolution microscopy techniques, such as stimulated emission depletion (STED), structured illumination microscopy (SIM), and single-molecule localization microscopy (SMLM), bypass the diffraction limit and provide a sub-diffraction-limit resolving power, ranging from 10 to 100 nm. The studies using super-resolution microscopy have revealed unprecedented details of the nanoscopic organization and dynamics of synaptic molecules. In general, most synaptic proteins appear to be heterogeneously distributed and form nanodomains at the membranes. These nanodomains are dynamic functional units, playing important roles in mediating signal transmission through synapses. Herein, we discuss our current knowledge on the super-resolution nanoscopic architecture of synapses and their functional implications, with a particular focus on the neuronal synapses and immune synapses.

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Beumer, Kelly, Heinrich J. G. Matthies, Amber Bradshaw, and Kendal Broadie. "Integrins regulate DLG/FAS2 via a CaM kinase II-dependent pathway to mediate synapse elaboration and stabilization during postembryonic development." Development 129, no. 14 (July 15, 2002): 3381–91. http://dx.doi.org/10.1242/dev.129.14.3381.

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Calcium/calmodulin dependent kinase II (CaMKII), PDZ-domain scaffolding protein Discs-large (DLG), immunoglobin superfamily cell adhesion molecule Fasciclin 2 (FAS2) and the position specific (PS) integrin receptors, including βPS and its alpha partners (αPS1, αPS2, αPS3/αVolado), are all known to regulate the postembryonic development of synaptic terminal arborization at the Drosophila neuromuscular junction (NMJ). Recent work has shown that DLG and FAS2 function together to modulate activity-dependent synaptic development and that this role is regulated by activation of CaMKII. We show that PS integrins function upstream of CaMKII in the development of synaptic architecture at the NMJ. βPS integrin physically associates with the synaptic complex anchored by the DLG scaffolding protein, which contains CaMKII and FAS2. We demonstrate an alteration of the FAS2 molecular cascade in integrin regulatory mutants, as a result of CaMKII/integrin interactions. Regulatory βPS integrin mutations increase the expression and synaptic localization of FAS2. Synaptic structural defects in βPS integrin mutants are rescued by transgenic overexpression of CaMKII (proximal in pathway) or genetic reduction of FAS2 (distal in pathway). These studies demonstrate that βPS integrins act through CaMKII activation to control the localization of synaptic proteins involved in the development of NMJ synaptic morphology.

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Chen, Xiumin, Yuko Fukata, Masaki Fukata, and Roger A. Nicoll. "MAGUKs are essential, but redundant, in long-term potentiation." Proceedings of the National Academy of Sciences 118, no. 28 (July 9, 2021): e2107585118. http://dx.doi.org/10.1073/pnas.2107585118.

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This study presents evidence that the MAGUK family of synaptic scaffolding proteins plays an essential, but redundant, role in long-term potentiation (LTP). The action of PSD-95, but not that of SAP102, requires the binding to the transsynaptic adhesion protein ADAM22, which is required for nanocolumn stabilization. Based on these and previous results, we propose a two-step process in the recruitment of AMPARs during LTP. First, AMPARs, via TARPs, bind to exposed PSD-95 in the PSD. This alone is not adequate to enhance synaptic transmission. Second, the AMPAR/TARP/PSD-95 complex is stabilized in the nanocolumn by binding to ADAM22. A second, ADAM22-independent pathway is proposed for SAP102.

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Sytnyk, Vladimir, Iryna Leshchyns'ka, Alexander G. Nikonenko, and Melitta Schachner. "NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex." Journal of Cell Biology 174, no. 7 (September 21, 2006): 1071–85. http://dx.doi.org/10.1083/jcb.200604145.

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The neural cell adhesion molecule (NCAM) regulates synapse formation and synaptic strength via mechanisms that have remained unknown. We show that NCAM associates with the postsynaptic spectrin-based scaffold, cross-linking NCAM with the N-methyl-d-aspartate (NMDA) receptor and Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) in a manner not firmly or directly linked to PSD95 and α-actinin. Clustering of NCAM promotes formation of detergent-insoluble complexes enriched in postsynaptic proteins and resembling postsynaptic densities. Disruption of the NCAM–spectrin complex decreases the size of postsynaptic densities and reduces synaptic targeting of NCAM–spectrin–associated postsynaptic proteins, including spectrin, NMDA receptors, and CaMKIIα. Degeneration of the spectrin scaffold in NCAM-deficient neurons results in an inability to recruit CaMKIIα to synapses after NMDA receptor activation, which is a critical process in NMDA receptor–dependent long-term potentiation. The combined observations indicate that NCAM promotes assembly of the spectrin-based postsynaptic signaling complex, which is required for activity-associated, long-lasting changes in synaptic strength. Its abnormal function may contribute to the etiology of neuropsychiatric disorders associated with mutations in or abnormal expression of NCAM.

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Yagishita-Kyo, Nan, Minami Harada, Tomoko Uekita, Kei Maruyama, Yuki Ikai, Chihiro Koshimoto, and Sosuke Yagishita. "The effect of sex hormones on the interaction between synaptic adhesion proteins concerned with sociality." Proceedings for Annual Meeting of The Japanese Pharmacological Society 92 (2019): 2—P—003. http://dx.doi.org/10.1254/jpssuppl.92.0_2-p-003.

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Taylor, Sara C., Sarah L. Ferri, Mahip Grewal, Zoe Smernoff, Maja Bucan, Joshua A. Weiner, Ted Abel, and Edward S. Brodkin. "The Role of Synaptic Cell Adhesion Molecules and Associated Scaffolding Proteins in Social Affiliative Behaviors." Biological Psychiatry 88, no. 6 (September 2020): 442–51. http://dx.doi.org/10.1016/j.biopsych.2020.02.012.

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Ali, Heba, Lena Marth, and Dilja Krueger-Burg. "Neuroligin-2 as a central organizer of inhibitory synapses in health and disease." Science Signaling 13, no. 663 (December 22, 2020): eabd8379. http://dx.doi.org/10.1126/scisignal.abd8379.

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Postsynaptic organizational protein complexes play central roles both in orchestrating synapse formation and in defining the functional properties of synaptic transmission that together shape the flow of information through neuronal networks. A key component of these organizational protein complexes is the family of synaptic adhesion proteins called neuroligins. Neuroligins form transsynaptic bridges with presynaptic neurexins to regulate various aspects of excitatory and inhibitory synaptic transmission. Neuroligin-2 (NLGN2) is the only member that acts exclusively at GABAergic inhibitory synapses. Altered expression and mutations in NLGN2 and several of its interacting partners are linked to cognitive and psychiatric disorders, including schizophrenia, autism, and anxiety. Research on NLGN2 has fundamentally shaped our understanding of the molecular architecture of inhibitory synapses. Here, we discuss the current knowledge on the molecular and cellular functions of mammalian NLGN2 and its role in the neuronal circuitry that regulates behavior in rodents and humans.

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Schmerl, Bettina, Niclas Gimber, Benno Kuropka, Alexander Stumpf, Jakob Rentsch, Stella-Amrei Kunde, Judith von Sivers, et al. "The synaptic scaffold protein MPP2 interacts with GABAA receptors at the periphery of the postsynaptic density of glutamatergic synapses." PLOS Biology 20, no. 3 (March 21, 2022): e3001503. http://dx.doi.org/10.1371/journal.pbio.3001503.

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Recent advances in imaging technology have highlighted that scaffold proteins and receptors are arranged in subsynaptic nanodomains. The synaptic membrane-associated guanylate kinase (MAGUK) scaffold protein membrane protein palmitoylated 2 (MPP2) is a component of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–associated protein complexes and also binds to the synaptic cell adhesion molecule SynCAM 1. Using superresolution imaging, we show that—like SynCAM 1—MPP2 is situated at the periphery of the postsynaptic density (PSD). In order to explore MPP2-associated protein complexes, we used a quantitative comparative proteomics approach and identified multiple γ-aminobutyric acid (GABA)A receptor subunits among novel synaptic MPP2 interactors. In line with a scaffold function for MPP2 in the assembly and/or modulation of intact GABAA receptors, manipulating MPP2 expression had effects on inhibitory synaptic transmission. We further show that GABAA receptors are found together with MPP2 in a subset of dendritic spines and thus highlight MPP2 as a scaffold that serves as an adaptor molecule, linking peripheral synaptic elements critical for inhibitory regulation to central structures at the PSD of glutamatergic synapses.

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Muellerleile, Julia, Matej Vnencak, Mohammad Valeed Ahmed Sethi, Tassilo Jungenitz, Stephan W. Schwarzacher, and Peter Jedlicka. "Increased Network Inhibition in the Dentate Gyrus of Adult Neuroligin-4 Knock-Out Mice." eneuro 10, no. 4 (April 2023): ENEURO.0471–22.2023. http://dx.doi.org/10.1523/eneuro.0471-22.2023.

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AbstractLoss-of-function mutations in neuroligin-4 (Nlgn4), a member of the neuroligin family of postsynaptic adhesion proteins, cause autism spectrum disorder in humans. Nlgn4 knockout (KO) in mice leads to social behavior deficits and complex alterations of synaptic inhibition or excitation, depending on the brain region. In the present work, we comprehensively analyzed synaptic function and plasticity at the cellular and network levels in hippocampal dentate gyrus of Nlgn4 KO mice. Compared with wild-type littermates, adult Nlgn4 KO mice exhibited increased paired-pulse inhibition of dentate granule cell population spikes, but no impairments in excitatory synaptic transmission or short-term and long-term plasticityin vivo.In vitropatch-clamp recordings in neonatal organotypic entorhino-hippocampal slice cultures from Nlgn4 KO and wild-type littermates revealed no significant differences in excitatory or inhibitory synaptic transmission, homeostatic synaptic plasticity, and passive electrotonic properties in dentate granule cells, suggesting that the increased inhibitionin vivois the result of altered network activity in the adult Nlgn4 KO. A comparison with prior studies on Nlgn 1–3 knock-out mice reveals that each of the four neuroligins exerts a characteristic effect on both intrinsic cellular and network activity in the dentate gyrusin vivo.

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Hsueh, Yi-Ping, Fu-Chia Yang, Viktor Kharazia, Scott Naisbitt, Alexandra R. Cohen, Richard J. Weinberg, and Morgan Sheng. "Direct Interaction of CASK/LIN-2 and Syndecan Heparan Sulfate Proteoglycan and Their Overlapping Distribution in Neuronal Synapses." Journal of Cell Biology 142, no. 1 (July 13, 1998): 139–51. http://dx.doi.org/10.1083/jcb.142.1.139.

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CASK, the rat homolog of a gene (LIN-2) required for vulval differentiation in Caenorhabditis elegans, is expressed in mammalian brain, but its function in neurons is unknown. CASK is distributed in a punctate somatodendritic pattern in neurons. By immunogold EM, CASK protein is concentrated in synapses, but is also present at nonsynaptic membranes and in intracellular compartments. This immunolocalization is consistent with biochemical studies showing the presence of CASK in soluble and synaptosomal membrane fractions and its enrichment in postsynaptic density fractions of rat brain. By yeast two-hybrid screening, a specific interaction was identified between the PDZ domain of CASK and the COOH terminal tail of syndecan-2, a cell surface heparan sulfate proteoglycan (HSPG). The interaction was confirmed by coimmunoprecipitation from heterologous cells. In brain, syndecan-2 localizes specifically at synaptic junctions where it shows overlapping distribution with CASK, consistent with an interaction between these proteins in synapses. Cell surface HSPGs can bind to extracellular matrix proteins, and are required for the action of various heparin-binding polypeptide growth/differentiation factors. The synaptic localization of CASK and syndecan suggests a potential role for these proteins in adhesion and signaling at neuronal synapses.

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Wright, John W., and Joseph W. Harding. "Contributions of Matrix Metalloproteinases to Neural Plasticity, Habituation, Associative Learning and Drug Addiction." Neural Plasticity 2009 (2009): 1–12. http://dx.doi.org/10.1155/2009/579382.

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The premise of this paper is that increased expression of matrix metalloproteinases (MMPs) permits the reconfiguration of synaptic connections (i.e., neural plasticity) by degrading cell adhesion molecules (CAMs) designed to provide stability to those extracellular matrix (ECM) proteins that form scaffolding supporting neurons and glia. It is presumed that while these ECM proteins are weakened, and/or detached, synaptic connections can form resulting in new neural pathways. Tissue inhibitors of metalloproteinases (TIMPs) are designed to deactivate MMPs permitting the reestablishment of CAMs, thus returning the system to a reasonably fixed state. This review considers available findings concerning the roles of MMPs and TIMPs in reorganizing ECM proteins thus facilitating the neural plasticity underlying long-term potentiation (LTP), habituation, and associative learning. We conclude with a consideration of the influence of these phenomena on drug addiction, given that these same processes may be instrumental in the formation of addiction and subsequent relapse. However, our knowledge concerning the precise spatial and temporal relationships among the mechanisms of neural plasticity, habituation, associative learning, and memory consolidation is far from complete and the possibility that these phenomena mediate drug addiction is a new direction of research.

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Lievens, Patricia Marie-Jeanne, Tatiana Kuznetsova, Gaga Kochlamazashvili, Fabrizia Cesca, Natalya Gorinski, Dalia Abdel Galil, Volodimir Cherkas, et al. "ZDHHC3 Tyrosine Phosphorylation Regulates Neural Cell Adhesion Molecule Palmitoylation." Molecular and Cellular Biology 36, no. 17 (May 31, 2016): 2208–25. http://dx.doi.org/10.1128/mcb.00144-16.

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The neural cell adhesion molecule (NCAM) mediates cell-cell and cell-matrix adhesion. It is broadly expressed in the nervous system and regulates neurite outgrowth, synaptogenesis, and synaptic plasticity. Previousin vitrostudies revealed that palmitoylation of NCAM is required for fibroblast growth factor 2 (FGF2)-stimulated neurite outgrowth and identified the zinc finger DHHC (Asp-His-His-Cys)-containing proteins ZDHHC3 and ZDHHC7 as specific NCAM-palmitoylating enzymes. Here, we verified that FGF2 controlled NCAM palmitoylationin vivoand investigated molecular mechanisms regulating NCAM palmitoylation by ZDHHC3. Experiments with overexpression and pharmacological inhibition of FGF receptor (FGFR) and Src revealed that these kinases control tyrosine phosphorylation of ZDHHC3 and that ZDHHC3 is phosphorylated by endogenously expressed FGFR and Src proteins. By site-directed mutagenesis, we found that Tyr18 is an FGFR1-specific ZDHHC3 phosphorylation site, while Tyr295 and Tyr297 are specifically phosphorylated by Src kinase in cell-based and cell-free assays. Abrogation of tyrosine phosphorylation increased ZDHHC3 autopalmitoylation, enhanced interaction with NCAM, and upregulated NCAM palmitoylation. Expression of ZDHHC3 with tyrosine mutated in cultured hippocampal neurons promoted neurite outgrowth. Our findings for the first time highlight that FGFR- and Src-mediated tyrosine phosphorylation of ZDHHC3 modulates ZDHHC3 enzymatic activity and plays a role in neuronal morphogenesis.

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Levinson, Joshua N., and Alaa El-Husseini. "New Players Tip the Scales in the Balance between Excitatory and Inhibitory Synapses." Molecular Pain 1 (January 1, 2005): 1744–8069. http://dx.doi.org/10.1186/1744-8069-1-12.

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Synaptogenesis is a highly controlled process, involving a vast array of players which include cell adhesion molecules, scaffolding and signaling proteins, neurotransmitter receptors and proteins associated with the synaptic vesicle machinery. These molecules cooperate in an intricate manner on both the pre- and postsynaptic sides to orchestrate the precise assembly of neuronal contacts. This is an amazing feat considering that a single neuron receives tens of thousands of synaptic inputs but virtually no mismatch between pre- and postsynaptic components occur in vivo. One crucial aspect of synapse formation is whether a nascent synapse will develop into an excitatory or inhibitory contact. The tight control of a balance between the types of synapses formed regulates the overall neuronal excitability, and is thus critical for normal brain function and plasticity. However, little is known about how this balance is achieved. This review discusses recent findings which provide clues to how neurons may control excitatory and inhibitory synapse formation, with focus on the involvement of the neuroligin family and PSD-95 in this process.

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Mizoguchi, Hiroyuki, Kiyofumi Yamada, and Toshitaka Nabeshima. "Matrix Metalloproteinases Contribute to Neuronal Dysfunction in Animal Models of Drug Dependence, Alzheimer's Disease, and Epilepsy." Biochemistry Research International 2011 (2011): 1–10. http://dx.doi.org/10.1155/2011/681385.

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Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors that mediate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Interestingly, increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathologic conditions. In this paper, we discuss various animal models that suggest that the activation of the gelatinases MMP-2 and MMP-9 is involved in pathogenesis of drug dependence, Alzheimer's disease, and epilepsy.

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Takano, Tetsuya. "Comprehensive identification of molecules at synapses and non-synaptic cell-adhesion structure." Impact 2023, no. 3 (September 21, 2023): 46–48. http://dx.doi.org/10.21820/23987073.2023.3.46.

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The brain is incredibly complex and there is so much we don't know about this organ and its mechanisms. Assistant Professor Tetsuya Takano, School of Medicine, Keio University, Japan, is working to better understand neuroscience. One area of interest is neurons and astrocytes; specifically elucidating the protein component functions in each neural circuit. He and his team are working to shed light on the pathological mechanism of psychiatric and neurological disorders and, in doing so, enabling improved treatments and benefiting patients across the globe. The team has developed spatio-temporal proteome technologies: TurboID-surface and Split-TurboID, that can not only explain the formation and operation principle of neural networks, but also provide essential knowledge for research into psychiatric and neurological diseases. To overcome limitations associated with conventional proteome analysis, Takano and the team recently developed a new in vivo proximal-dependent biotin labelling (BioID) method. Using this, the researchers can label and analyse adjacent proteins with biotin, which enables them to comprehensively analyse local protein components within cells with extremely high spatial resolution. The team has used the BioID method to develop the Split-TurboID method and an innovative spatial proteome technique for searching for molecular groups among heterogeneous cells that makes it possible to comprehensively analyse the protein components in the vicinity of the adhesion site. Using the Split-TurboID method, the team has comprehensively searched for functional molecules between astrocytes and neurons and revealed that astrocytes directly control the formation of inhibitory synapses and neuronal activity in neurons via a novel tripartite synaptic molecule known as NRCAM.

Journal articles on the topic 'Synaptic adhesion proteins'

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