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Hu, Xiaoge, Jian-hong Luo e 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.
Testo completoAbstract (sommario):
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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Pettem, Katherine L., Daisaku Yokomaku, Hideto Takahashi, Yuan Ge e Ann Marie Craig. "Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development". Journal of Cell Biology 200, n. 3 (28 gennaio 2013): 321–36. http://dx.doi.org/10.1083/jcb.201206028.
Testo completoAbstract (sommario):
Rare variants in MDGAs (MAM domain–containing glycosylphosphatidylinositol anchors), including multiple protein-truncating deletions, are linked to autism and schizophrenia, but the function of these genes is poorly understood. Here, we show that MDGA1 and MDGA2 bound to neuroligin-2 inhibitory synapse–organizing protein, also implicated in neurodevelopmental disorders. MDGA1 inhibited the synapse-promoting activity of neuroligin-2, without altering neuroligin-2 surface trafficking, by inhibiting interaction of neuroligin-2 with neurexin. MDGA binding and suppression of synaptogenic activity was selective for neuroligin-2 and not neuroligin-1 excitatory synapse organizer. Overexpression of MDGA1 in cultured rat hippocampal neurons reduced inhibitory synapse density without altering excitatory synapse density. Furthermore, RNAi-mediated knockdown of MDGA1 selectively increased inhibitory but not excitatory synapse density. These results identify MDGA1 as one of few identified negative regulators of synapse development with a unique selectivity for inhibitory synapses. These results also place MDGAs in the neurexin–neuroligin synaptic pathway implicated in neurodevelopmental disorders and support the idea that an imbalance between inhibitory and excitatory synapses may contribute to these disorders.
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Ko, Jaewon, Gilberto J. Soler-Llavina, Marc V. Fuccillo, Robert C. Malenka e Thomas C. Südhof. "Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons". Journal of Cell Biology 194, n. 2 (25 luglio 2011): 323–34. http://dx.doi.org/10.1083/jcb.201101072.
Testo completoAbstract (sommario):
Neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs) are postsynaptic cell adhesion molecules that bind to presynaptic neurexins. In this paper, we show that short hairpin ribonucleic acid–mediated knockdowns (KDs) of LRRTM1, LRRTM2, and/or NL-3, alone or together as double or triple KDs (TKDs) in cultured hippocampal neurons, did not decrease synapse numbers. In neurons cultured from NL-1 knockout mice, however, TKD of LRRTMs and NL-3 induced an ∼40% loss of excitatory but not inhibitory synapses. Strikingly, synapse loss triggered by the LRRTM/NL deficiency was abrogated by chronic blockade of synaptic activity as well as by chronic inhibition of Ca2+ influx or Ca2+/calmodulin (CaM) kinases. Furthermore, postsynaptic KD of CaM prevented synapse loss in a cell-autonomous manner, an effect that was reversed by CaM rescue. Our results suggest that two neurexin ligands, LRRTMs and NLs, act redundantly to maintain excitatory synapses and that synapse elimination caused by the absence of NLs and LRRTMs is promoted by synaptic activity and mediated by a postsynaptic Ca2+/CaM-dependent signaling pathway.
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Gaidarova, Svetlana, JianWu Li, Laura G. Corral, Emilia Glezer, Peter H. Schafer, Weilin Xie, Antonia Lopez-Girona, Bruce D. Cheson e Brydon Bennett. "Lenalidomide Alone and in Combination with Rituximab Enhances NK Cell Immune Synapse Formation in Chronic Lymphocytic Leukemia (CLL) Cells in Vitro through Activation of Rho and Rac1 GTPases." Blood 114, n. 22 (20 novembre 2009): 3441. http://dx.doi.org/10.1182/blood.v114.22.3441.3441.
Testo completoAbstract (sommario):
Abstract Abstract 3441 Poster Board III-329 Background CLL is characterized by the progressive accumulation of monoclonal B lymphocytes. One theory to explain how CLL cells avoid elimination through immune surveillance mechanisms is through a defect in the ability of T-cells to form immunological synapses with antigen-presenting tumor B-cells (Ramsay et al JCI 2008). Lenalidomide is an immunomodulatory agent with clinical activity in the treatment of B-cell malignancies. Recent laboratory studies showed that lenalidomide not only stimulates T- and natural killer (NK)-cell-mediated ADCC, it also restores the T-cell-mediated ability to form immunological synapses with CLL tumor cells. Since NK cells also exert cytotoxicity through immune synapse formation, here we explore how lenalidomide affects NK-cell-mediated cytotoxicity mechanisms and whether this activity is altered in the presence of rituximab since published studies showed that lenalidomide-pretreated B-cells have a down-regulated surface CD20 expression. Further, we investigated the molecular events associated with immune synapse formation and the effect of lenalidomide. Methods Immune synapse formation was assessed in NK cells (from healthy donors PBMCs) co-cultured with either B-CLL cells derived from pts or with K562 cells (positive control). Cells were fixed and the ability to form synapses was assessed via immunohistochemisty co-staining for either F-actin and CD2, or F-actin and perforin (a cytolytic protein found in NK cells). Synapse formation was visualized by microscopy and measured via relative mean fluorescent intensity. Activity of RhoA, Rac1, Cdc42 were measured using Rho GTPases assay kits. Inhibition of lenalidomide-mediated immune synapse activity was assayed using the cell permeable Rho inhibitor C3 (0.5 mM). Flow cytometry was used to measure changes in surface CD20 and CD54 (ICAM-1) expression in B-CLL samples from 3 pts after treatment with lenalidomide. Results Lenalidomide induced the formation of immunological synapses between NK cells and primary B-CLL cells (p<.01) or the K562 cell line. Lenalidomide activated NK cells regardless of the presence of target cells, as measured by F-actin and perforin staining. RhoA and Rac1 were activated at the immunological synapse in the presence of lenalidomide. Inhibition of RhoA by the C3 inhibitor blocked F-actin localization, as well as perforin accumulation induced by lenalidomide at cell-cell contact sites, indicating inhibition of immune synapses and the associated cytolytic activity. This was also observed with Rac1 inhibition, but to a lesser degree than with RhoA inhibition. Functionality of formed synapses was confirmed by co-localization of F-actin and perforin at the synapse sites. 3 CLL pt samples treated ex vivo with lenalidomide demonstrated variable changes in CD20 expression: a 20-30% decrease in CD20 expression was observed in 2 B-CLL pt samples, whereas CD20 levels remained unchanged in the third. In the presence of rituximab, lenalidomide-induced synapse formation between NK cells and B-cells from CLL patients was further enhanced. This was accompanied by upregulation of costimulatory and adhesion molecule CD54 on B-CLL cells suggesting increased antigen presentation, which might contribute to the increased synapse formation. Conclusion Lenalidomide can directly activate NK-cell-mediated anti-tumor activity through enhanced formation of immune synapses via the regulation of Rho and Rac1 GTPases and the cytoskeleton. Despite some down-modulation of CD20 expression in lenalidomide-pretreated B-CLL cells, the immune synapse activity increases when lenalidomide is combined with rituximab suggesting that combining lenalidomide and anti-CD20 antibodies warrants exploration in the CLL clinical setting. Disclosures Gaidarova: Celgene: Employment, Equity Ownership. Li:Celgene: Employment. Corral:Celgene: Employment. Glezer:Celgene: Employment, Equity Ownership. Schafer:Celgene: Employment. Xie:Celgene: Employment. Lopez-Girona:Celgene: Employment.
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Moss, Brenda L., Abby D. Fuller, Christie L. Sahley e Brian D. Burrell. "Serotonin Modulates Axo-Axonal Coupling Between Neurons Critical for Learning in the Leech". Journal of Neurophysiology 94, n. 4 (ottobre 2005): 2575–89. http://dx.doi.org/10.1152/jn.00322.2005.
Testo completoAbstract (sommario):
S cells form a chain of electrically coupled neurons that extends the length of the leech CNS and plays a critical role in sensitization during whole-body shortening. This process requires serotonin, which acts in part by altering the pattern of activity in the S-cell network. Serotonin-containing axons and varicosities were observed in Faivre's nerve where the S-to-S-cell electrical synapses are located. To determine whether serotonin modulates these synapses, S-cell action-potential (AP) propagation was studied in a two-ganglion chain containing one electrical synapse. Suction electrodes were placed on the cut ends of the connectives to stimulate one S cell while recording the other, coupled S cell's APs. A third electrode, placed en passant, recorded the APs near the electrical synapse before they propagated through it. Low concentrations of the gap junction inhibitor octanol increased AP latency across the two-ganglion chain, and this effect was localized to the region of axon containing the electrical synapse. At higher concentrations, APs failed to propagate across the synapse. Serotonin also increased AP latency across the electrical synapse, suggesting that serotonin reduced coupling between S cells. This effect was independent of the direction of propagation and increased with the number of electrical synapses in progressively longer chains. Furthermore, serotonin modulated instantaneous AP frequency when APs were initiated in separate S cells and in a computational model of S-cell activity after mechanosensory input. Thus serotonergic modulation of S-cell electrical synapses may contribute to changes in the pattern of activity in the S-cell network.
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Wei, Wei, e Xiao-Jing Wang. "Downstream Effect of Ramping Neuronal Activity through Synapses with Short-Term Plasticity". Neural Computation 28, n. 4 (aprile 2016): 652–66. http://dx.doi.org/10.1162/neco_a_00818.
Testo completoAbstract (sommario):
Ramping neuronal activity refers to spiking activity with a rate that increases quasi-linearly over time. It has been observed in multiple cortical areas and is correlated with evidence accumulation processes or timing. In this work, we investigated the downstream effect of ramping neuronal activity through synapses that display short-term facilitation (STF) or depression (STD). We obtained an analytical result for a synapse driven by deterministic linear ramping input that exhibits pure STF or STD and numerically investigated the general case when a synapse displays both STF and STD. We show that the analytical deterministic solution gives an accurate description of the averaging synaptic activation of many inputs converging onto a postsynaptic neuron, even when fluctuations in the ramping input are strong. Activation of a synapse with STF shows an initial cubical increase with time, followed by a linear ramping similar to a synapse without STF. Activation of a synapse with STD grows in time to a maximum before falling and reaching a plateau, and this steady state is independent of the slope of the ramping input. For a synapse displaying both STF and STD, an increase in the depression time constant from a value much smaller than the facilitation time constant [Formula: see text] to a value much larger than [Formula: see text] leads to a transition from facilitation dominance to depression dominance. Therefore, our work provides insights into the impact of ramping neuronal activity on downstream neurons through synapses that display short-term plasticity. In a perceptual decision-making process, ramping activity has been observed in the parietal and prefrontal cortices, with a slope that decreases with task difficulty. Our work predicts that neurons downstream from such a decision circuit could instead display a firing plateau independent of the task difficulty, provided that the synaptic connection is endowed with short-term depression.
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Liu, Kang K. L., Michael F. Hagan e John E. Lisman. "Gradation (approx. 10 size states) of synaptic strength by quantal addition of structural modules". Philosophical Transactions of the Royal Society B: Biological Sciences 372, n. 1715 (5 marzo 2017): 20160328. http://dx.doi.org/10.1098/rstb.2016.0328.
Testo completoAbstract (sommario):
Memory storage involves activity-dependent strengthening of synaptic transmission, a process termed long-term potentiation (LTP). The late phase of LTP is thought to encode long-term memory and involves structural processes that enlarge the synapse. Hence, understanding how synapse size is graded provides fundamental information about the information storage capability of synapses. Recent work using electron microscopy (EM) to quantify synapse dimensions has suggested that synapses may structurally encode as many as 26 functionally distinct states, which correspond to a series of proportionally spaced synapse sizes. Other recent evidence using super-resolution microscopy has revealed that synapses are composed of stereotyped nanoclusters of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and scaffolding proteins; furthermore, synapse size varies linearly with the number of nanoclusters. Here we have sought to develop a model of synapse structure and growth that is consistent with both the EM and super-resolution data. We argue that synapses are composed of modules consisting of matrix material and potentially one nanocluster. LTP induction can add a trans-synaptic nanocluster to a module, thereby converting a silent module to an AMPA functional module. LTP can also add modules by a linear process, thereby producing an approximately 10-fold gradation in synapse size and strength. This article is part of the themed issue ‘Integrating Hebbian and homeostatic plasticity’.
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Zhao, Qing-Tai, Fengben Xi, Yi Han, Andreas Grenmyr, Jin Hee Bae e Detlev Gruetzmacher. "Ferroelectric Devices for Neuromorphic Computing". ECS Meeting Abstracts MA2022-02, n. 32 (9 ottobre 2022): 1183. http://dx.doi.org/10.1149/ma2022-02321183mtgabs.
Testo completoAbstract (sommario):
Neuromorphic computing inspired by the neural network systems of the human brain enables energy efficient computing for big-data processing. A neural network is formed by thousands or even millions of neurons which are connected by even a higher number of synapses. Neurons communicate with each other through the connected synapses. The main responsibility of synapses is to transfer information from the pre-synaptic to the postsynaptic neurons. Synapses can memorize and process the information simultaneously. The plasticity of a synapse to strengthen or weaken their activity over time make it capable of learning and computing. Thus, artificial synapses which can emulate functionalities and the plasticity of bio-synapses form the backbones of neuromorphic computing. Alternative artificial synapses have been successfully demonstrated. The classical two-terminal memristor devices, like resistive random access memory (ReRAM), phase change memory (PCM) and ferroelectric tunnel junctions (FTJs) with one terminal connected to the pre-synaptic neuron and another connected with the post-synaptic neuron, own advantages of simple structure, easy processing with high density, and capability of integration with CMOS. However, signal processing and learning cannot be performed simultaneously in 2-terminal devices, thus limiting their synaptic functionalities. Ferroelectric field effect transistors (FeFET) which uses ferroelectric as the gate oxide are the most interesting three-terminal artificial synapse devices, in which the gate or the source is connected to the pre-synaptic neuron while the drain is used for the terminal of the post-synaptic neuron , thus can perform signal transmission and learning simultaneously. However, traps at the channel interface can degrade the device performance causing low endurance. Focuses of those abovementioned devices have been mainly put on the homosynaptic plasticity, which is input specific, meaning that the plasticity occurs only at the synapse with a pre-synaptic activation . The homosynaptic plasticity has a drawback of positive feedback loop: when a synapse is potentiated, the probability of the synapse to be further potentiated is increased. Similarly, when a synapse is depressed the probability of the synapse of being further depressed is higher. Therefore, synaptic weights tend to be either strengthened to the maximum value or weakened to zero, causing the system to be unstable. In contrast, heterosynaptic plasticity can be induced at any synapse at the same time after episodes of strong postsynaptic activity, avoiding the positive feedback problem and stabilize the activity of the post-synaptic neuron. To address the above challenges we proposed a very simple 4-terminal synapse structure based on gated Schottky diodes on silicon (FEMOD) with a ferroelectric layer. The conductance of the Schottky diode is modulated by the polarization of the ferroelectric layer. With this simple synapse structure we can achieve multiple hetero-synaptic functions, including excitatory/ inhibitory post-synaptic current (EPSC/IPSC), paired-pulse facilitation/depression (PPF/PPD), long-term potentiation/depression (LTP/LTD), as well as biological neuron-like spike-timing-dependent plasticity (STDP) characteristics. The modulatory synapse can modify the weight of another synapse with a very low voltage. Furthermore, logic gates, like AND and NAND which are highly desired for in-memory computing can be realized with such simple structure. Figure 1
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Wilson, Emily S., e Karen Newell-Litwa. "Stem cell models of human synapse development and degeneration". Molecular Biology of the Cell 29, n. 24 (26 novembre 2018): 2913–21. http://dx.doi.org/10.1091/mbc.e18-04-0222.
Testo completoAbstract (sommario):
Many brain disorders exhibit altered synapse formation in development or synapse loss with age. To understand the complexities of human synapse development and degeneration, scientists now engineer neurons and brain organoids from human-induced pluripotent stem cells (hIPSC). These hIPSC-derived brain models develop both excitatory and inhibitory synapses and functional synaptic activity. In this review, we address the ability of hIPSC-derived brain models to recapitulate synapse development and insights gained into the molecular mechanisms underlying synaptic alterations in neuronal disorders. We also discuss the potential for more accurate human brain models to advance our understanding of synapse development, degeneration, and therapeutic responses.
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Bloom, Ona, Emma Evergren, Nikolay Tomilin, Ole Kjaerulff, Peter Löw, Lennart Brodin, Vincent A. Pieribone, Paul Greengard e Oleg Shupliakov. "Colocalization of synapsin and actin during synaptic vesicle recycling". Journal of Cell Biology 161, n. 4 (19 maggio 2003): 737–47. http://dx.doi.org/10.1083/jcb.200212140.
Testo completoAbstract (sommario):
It has been hypothesized that in the mature nerve terminal, interactions between synapsin and actin regulate the clustering of synaptic vesicles and the availability of vesicles for release during synaptic activity. Here, we have used immunogold electron microscopy to examine the subcellular localization of actin and synapsin in the giant synapse in lamprey at different states of synaptic activity. In agreement with earlier observations, in synapses at rest, synapsin immunoreactivity was preferentially localized to a portion of the vesicle cluster distal to the active zone. During synaptic activity, however, synapsin was detected in the pool of vesicles proximal to the active zone. In addition, actin and synapsin were found colocalized in a dynamic filamentous cytomatrix at the sites of synaptic vesicle recycling, endocytic zones. Synapsin immunolabeling was not associated with clathrin-coated intermediates but was found on vesicles that appeared to be recycling back to the cluster. Disruption of synapsin function by microinjection of antisynapsin antibodies resulted in a prominent reduction of the cytomatrix at endocytic zones of active synapses. Our data suggest that in addition to its known function in clustering of vesicles in the reserve pool, synapsin migrates from the synaptic vesicle cluster and participates in the organization of the actin-rich cytomatrix in the endocytic zone during synaptic activity.
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Kruyer, Anna. "Astrocyte Heterogeneity in Regulation of Synaptic Activity". Cells 11, n. 19 (5 ottobre 2022): 3135. http://dx.doi.org/10.3390/cells11193135.
Testo completoAbstract (sommario):
Our awareness of the number of synapse regulatory functions performed by astroglia is rapidly expanding, raising interesting questions regarding astrocyte heterogeneity and specialization across brain regions. Whether all astrocytes are poised to signal in a multitude of ways, or are instead tuned to surrounding synapses and how astroglial signaling is altered in psychiatric and cognitive disorders are fundamental questions for the field. In recent years, molecular and morphological characterization of astroglial types has broadened our ability to design studies to better analyze and manipulate specific functions of astroglia. Recent data emerging from these studies will be discussed in depth in this review. I also highlight remaining questions emerging from new techniques recently applied toward understanding the roles of astrocytes in synapse regulation in the adult brain.
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Liu, Y., R. D. Fields, S. Fitzgerald, B. W. Festoff e P. G. Nelson. "Proteolytic activity, synapse elimination, and the Hebb synapse". Journal of Neurobiology 25, n. 3 (marzo 1994): 325–35. http://dx.doi.org/10.1002/neu.480250312.
Testo completo
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Apollonio, Benedetta, Mariam Fanous, Mohamed-Reda Benmebarek, Stephen Devereux, Patrick Hagner, Michael Pourdehnad, Anita K. Gandhi, Piers E. Patten e Alan G. Ramsay. "CC-122 Repairs T Cell Activation in Chronic Lymphocytic Leukemia That Results in a Concomitant Increase in PD-1:PD-L1 and CTLA-4 Immune Checkpoint Expression at the Immunological Synapse". Blood 126, n. 23 (3 dicembre 2015): 1738. http://dx.doi.org/10.1182/blood.v126.23.1738.1738.
Testo completoAbstract (sommario):
Abstract Immunomodulatory drugs (IMiDs®) such as lenalidomide and immune checkpoint blockade (ICB) antibodies can enhance autologous anti-tumor T cell immunity and have the potential to elicit durable control of disease in B cell malignancies. These immunotherapies are likely to be most effective when employed in treatment combinations. Thus, the goal of pre-clinical research should be to reveal mechanisms of action (MOA) in the tumor microenvironment (TME) and identify biomarkers to guide development of combination therapy for patients. CC-122 is a novel first-in-class pleiotropic pathway modifier (PPM®) that has potent anti-proliferative, anti-angiogenic and immunomodulatory activities and is currently in Phase I clinical trials for lymphoma and chronic lymphocytic leukemia (CLL). Here, we have utilized the immunological synapse bioassay to examine T cell interactions with CLL tumor cells (modeling anti-tumor T cell responses in the TME) following CC-122 treatment and measure the expression of co-signaling complexes at the synapse. Conjugation assays and confocal imaging were used to visualize intercellular conjugate interactions and F-actin polymerization at the immune synapse between CD4+ and CD8+ T cells and autologous CLL tumor cells pulsed with superantigen (acting as antigen-presenting cells, APCs). Peripheral blood was obtained from treatment naive CLL patients (n=40) representative of disease heterogeneity. Treatment of both purified CLL cells and CD4+ or CD8+ T cells with CC-122 (0.01 - 1 μM for 24h) dramatically enhanced the number of T cells recognizing tumor cells (% conjugation) and increased the formation of F-actin immune synapses (area, μm2) compared to vehicle treated cells (P<.01). Notably, CC-122 treatment induced T cells to engage in multiple tumor cell synapse interactions that were more pronounced in restored CD8+ T cell lytic synapses. This immunomodulatory activity was detected across all CLL patient samples and drug concentrations tested. In addition, synapse strength as measured by total fluorescence intensity of F-actin per T cell:APC conjugate increased significantly with CC-122 (P<.01). A critical MOA of lenalidomide is activation of T cell immune synapse signaling. Here, our comparative studies revealed that CC-122 (0.1 - 1 μM) significantly enhanced autologous T cell synapse activity in CLL by 4 - 5 fold versus vehicle (P<.01), whereas lenalidomide (1 μM) enhanced activity by 3 fold vs vehicle. Moreover, CC-122 treatment resulted in increased expression and polarization of tyrosine-phosphorylated proteins at T cell synapses compared to lenalidomide and vehicle treatment (P<.01). This data provides evidence that CC-122 induces functional T cell synapses that control the assembly of signaling complexes between the T cell receptor (TCR) and the F-actin cytoskeletal layer. Following T cell recognition of APCs, co-signaling receptors co-localize at the immune synapse where they synergize with TCR signaling to promote (co-stimulatory receptors) or inhibit (co-inhibitory/'immune checkpoint' receptors) T cell activation. Quantitative image analysis studies revealed that restoration of T cell synapse activity with CC-122 was accompanied by an increased recruitment of inducible co-stimulator (ICOS) to the synapse that was dose-dependent (P<.01). CC-122 treatment also increased polarized expression of CTLA-4 and PD-1 immune checkpoint proteins at the synapse with PD-L1+ tumor cells. The observed up-regulation of co-inhibitory receptors led to combining CC-122 with anti-PD-L1, anti-PD-1 or anti-CTLA-4 blocking antibodies. Results show that these treatment combinations increased T cell synapse activity compared to using these immunotherapies alone (P<.01). In conclusion, our results demonstrate for the first time that CC-122 can activate T cell immune synapse signaling against autologous CLL tumor cells and this immunomodulatory capability is more potent than lenalidomide. We further show that CC-122 activation of T cells is associated with enhanced expression of the co-stimulatory receptor ICOS and co-inhibitory checkpoints CTLA-4 and PD-1 at the synapse site. Importantly, our pre-clinical data demonstrates that this regulatory feedback inhibition can be exploited by the addition of anti-PD-L1, anti-PD-1 or anti-CTLA-4 ICB to CC-122 to more optimally stimulate T cell activity against immunosuppressive tumor cells. Disclosures Hagner: Celgene: Employment, Equity Ownership. Pourdehnad:Celgene: Employment. Gandhi:Celgene: Employment, Equity Ownership. Ramsay:MedImmune: Research Funding; Celgene: Research Funding.
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Mamiya, Akira, e Farzan Nadim. "Target-Specific Short-Term Dynamics Are Important for the Function of Synapses in an Oscillatory Neural Network". Journal of Neurophysiology 94, n. 4 (ottobre 2005): 2590–602. http://dx.doi.org/10.1152/jn.00110.2005.
Testo completoAbstract (sommario):
Short-term dynamics such as facilitation and depression are present in most synapses and are often target-specific even for synapses from the same type of neuron. We examine the dynamics and possible functions of two synapses from the same presynaptic neuron in the rhythmically active pyloric network of the spiny lobster. Using simultaneous recordings, we show that the synapses from the lateral pyloric (LP) neuron to the pyloric dilator (PD; a member of the pyloric pacemaker ensemble) and the pyloric constrictor (PY) neurons both show short-term depression. However, the postsynaptic potentials produced by the LP-to-PD synapse are larger in amplitude, depress less, and recover faster than those produced by the LP-to-PY synapse. The main function of the LP-to-PD synapse is to slow down the pyloric rhythm. However, in some cases, it slows down the rhythm only when it is fast and has no effect or to speeds up when it is slow. In contrast, the LP-to-PY synapse functions to delay the activity of the PY neuron; this delay increases as the cycle period becomes longer. Using a computational model, we show that the short-term dynamics of synaptic depression observed for each of these synapses are tailored to their individual functions and that replacing the dynamics of either synapse with the other would disrupt these functions. Together, the experimental and modeling results suggest that the target-specific features of short-term synaptic depression are functionally important for synapses efferent from the same presynaptic neuron.
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Wang, Fei, Qianqian Wang, Baowei Liu, Lisheng Mei, Sisi Ma, Shujuan Wang, Ruoyu Wang et al. "The long noncoding RNA Synage regulates synapse stability and neuronal function in the cerebellum". Cell Death & Differentiation 28, n. 9 (24 marzo 2021): 2634–50. http://dx.doi.org/10.1038/s41418-021-00774-3.
Testo completoAbstract (sommario):
AbstractThe brain is known to express many long noncoding RNAs (lncRNAs); however, whether and how these lncRNAs function in modulating synaptic stability remains unclear. Here, we report a cerebellum highly expressed lncRNA, Synage, regulating synaptic stability via at least two mechanisms. One is through the function of Synage as a sponge for the microRNA miR-325-3p, to regulate expression of the known cerebellar synapse organizer Cbln1. The other function is to serve as a scaffold for organizing the assembly of the LRP1-HSP90AA1-PSD-95 complex in PF-PC synapses. Although somewhat divergent in its mature mRNA sequence, the locus encoding Synage is positioned adjacent to the Cbln1 loci in mouse, rhesus macaque, and human, and Synage is highly expressed in the cerebella of all three species. Synage deletion causes a full-spectrum cerebellar ablation phenotype that proceeds from cerebellar atrophy, through neuron loss, on to synapse density reduction, synaptic vesicle loss, and finally to a reduction in synaptic activity during cerebellar development; these deficits are accompanied by motor dysfunction in adult mice, which can be rescued by AAV-mediated Synage overexpression from birth. Thus, our study demonstrates roles for the lncRNA Synage in regulating synaptic stability and function during cerebellar development.
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Chattopadhyaya, Bidisha. "Molecular Mechanisms Underlying Activity-Dependent GABAergic Synapse Development and Plasticity and Its Implications for Neurodevelopmental Disorders". Neural Plasticity 2011 (2011): 1–8. http://dx.doi.org/10.1155/2011/734231.
Testo completoAbstract (sommario):
GABAergic interneurons are critical for the normal function and development of neural circuits, and their dysfunction is implicated in a large number of neurodevelopmental disorders. Experience and activity-dependent mechanisms play an important role in GABAergic circuit development, also recent studies involve a number of molecular players involved in the process. Emphasizing the molecular mechanisms of GABAergic synapse formation, in particular basket cell perisomatic synapses, this paper draws attention to the links between critical period plasticity, GABAergic synapse maturation, and the consequences of its dysfunction on the development of the nervous system.
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Staple, Julie K., Florence Morgenthaler e Stefan Catsicas. "Presynaptic Heterogeneity: Vive la difference". Physiology 15, n. 1 (febbraio 2000): 45–49. http://dx.doi.org/10.1152/physiologyonline.2000.15.1.45.
Testo completoAbstract (sommario):
Since individual synapses of the same neuron may have different molecular composition, an important question in neurobiology is how the properties of individual synapses are established and maintained. Recent technical advances allow assay of activity at individual synapses and investigation of the relationship between function and molecular composition at the synapse.
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Brodin, Lennart, Lora Bakeeva e Oleg Shupliakov. "Presynaptic mitochondria and the temporal pattern of neurotransmitter release". Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 354, n. 1381 (28 febbraio 1999): 365–72. http://dx.doi.org/10.1098/rstb.1999.0388.
Testo completoAbstract (sommario):
Mitochondria are critical for the function of nerve terminals as the cycling of synaptic vesicle membrane requires an efficient supply of ATP. In addition, the presynaptic mitochondria take part in functions such as Ca 2+ buffering and neurotransmitter synthesis. To learn more about presynaptic mitochondria, we have examined their organization in two types of synapse in the lamprey, both of which are glutamatergic but are adapted to different temporal patterns of activity. The first is the giant lamprey reticulospinal synapse, which is specialized to transmit phasic signals (i.e. bursts of impulses). The second is the synapse established by sensory dorsal column axons, which is adapted to tonic activity. In both cases, the presynaptic axons were found to contain two distinct types of mitochondria; small ‘synaptic’ mitochondria, located near release sites, and larger mitochondria located in more central parts of the axon. The size of the synapse–associated mitochondria was similar in both types of synapse. However, their number differed considerably. Whereas the reticulospinal synapses contained only single mitochondria within 1 micrometre distance from the edge of the active zone (on average 1.2 per active zone, range of 1–3), the tonic dorsal column synapses were surrounded by clusters of mitochondria (4.5 per active zone, range of 3–6), with individual mitochondria sometimes apparently connected by intermitochondrial contacts. In conjunction with studies of crustacean neuromuscular junctions, these observations indicate that the temporal pattern of transmitter release is an important determinant of the organization of presynaptic mitochondria.
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Stevens-Sostre, Whitney A., e Mrinalini Hoon. "Cellular and Molecular Mechanisms Regulating Retinal Synapse Development". Annual Review of Vision Science 10, n. 1 (15 settembre 2024): 377–402. http://dx.doi.org/10.1146/annurev-vision-102122-105721.
Testo completoAbstract (sommario):
Synapse formation within the retinal circuit ensures that distinct neuronal types can communicate efficiently to process visual signals. Synapses thus form the core of the visual computations performed by the retinal circuit. Retinal synapses are diverse but can be broadly categorized into multipartner ribbon synapses and 1:1 conventional synapses. In this article, we review our current understanding of the cellular and molecular mechanisms that regulate the functional establishment of mammalian retinal synapses, including the role of adhesion proteins, synaptic proteins, extracellular matrix and cytoskeletal-associated proteins, and activity-dependent cues. We outline future directions and areas of research that will expand our knowledge of these mechanisms. Understanding the regulators moderating synapse formation and function not only reveals the integrated developmental processes that establish retinal circuits, but also divulges the identity of mechanisms that could be engaged during disease and degeneration.
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Flores, Carmen E., Irina Nikonenko, Pablo Mendez, Jean-Marc Fritschy, Shiva K. Tyagarajan e Dominique Muller. "Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation". Proceedings of the National Academy of Sciences 112, n. 1 (22 dicembre 2014): E65—E72. http://dx.doi.org/10.1073/pnas.1411170112.
Testo completoAbstract (sommario):
Maintaining a proper balance between excitation and inhibition is essential for the functioning of neuronal networks. However, little is known about the mechanisms through which excitatory activity can affect inhibitory synapse plasticity. Here we used tagged gephyrin, one of the main scaffolding proteins of the postsynaptic density at GABAergic synapses, to monitor the activity-dependent adaptation of perisomatic inhibitory synapses over prolonged periods of time in hippocampal slice cultures. We find that learning-related activity patterns known to induce N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation and transient optogenetic activation of single neurons induce within hours a robust increase in the formation and size of gephyrin-tagged clusters at inhibitory synapses identified by correlated confocal electron microscopy. This inhibitory morphological plasticity was associated with an increase in spontaneous inhibitory activity but did not require activation of GABAA receptors. Importantly, this activity-dependent inhibitory plasticity was prevented by pharmacological blockade of Ca2+/calmodulin-dependent protein kinase II (CaMKII), it was associated with an increased phosphorylation of gephyrin on a site targeted by CaMKII, and could be prevented or mimicked by gephyrin phospho-mutants for this site. These results reveal a homeostatic mechanism through which activity regulates the dynamics and function of perisomatic inhibitory synapses, and they identify a CaMKII-dependent phosphorylation site on gephyrin as critically important for this process.
21
Ji, Kyungmin, Jeremy Miyauchi e Stella E. Tsirka. "Microglia: An Active Player in the Regulation of Synaptic Activity". Neural Plasticity 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/627325.
Testo completoAbstract (sommario):
Synaptic plasticity is critical for elaboration and adaptation in the developing and developed brain. It is well established that astrocytes play an important role in the maintenance of what has been dubbed “the tripartite synapse”. Increasing evidence shows that a fourth cell type, microglia, is critical to this maintenance as well. Microglia are the resident macrophages of the central nervous system (CNS). Because of their well-characterized inflammatory functions, research has primarily focused on their innate immune properties. The role of microglia in the maintenance of synapses in development and in homeostasis is not as well defined. A number of significant findings have shed light on the critical role of microglia at the synapse. It is becoming increasingly clear that microglia play a seminal role in proper synaptic development and elimination.
22
Lalo, Ulyana, Jemma Andrew, Oleg Palygin e Yuriy Pankratov. "Ca2+-dependent modulation of GABAA and NMDA receptors by extracellular ATP: implication for function of tripartite synapse". Biochemical Society Transactions 37, n. 6 (19 novembre 2009): 1407–11. http://dx.doi.org/10.1042/bst0371407.
Testo completoAbstract (sommario):
The importance of communication between neuronal and glial cells for brain function is recognized by a modern concept of ‘tripartite synapse’. Astrocytes enwrap synapses and can modulate their activity by releasing gliotransmitters such as ATP, glutamate and D-serine. One of the regulatory pathways in the tripartite synapse is mediated by P2X purinoreceptors. Release of ATP from synaptic terminals and astrocytes activates Ca2+ influx via P2X purinoreceptors which co-localize with NMDA (N-methyl-D-aspartate) and GABA (γ-aminobutyric acid) receptors and can modulate their activity via intracellular cascades which involve phosphatase II and PKA (protein kinase A).
23
Lee, Sang-Eun, Yoonju Kim, Jeong-Kyu Han, Hoyong Park, Unghwi Lee, Myeongsu Na, Soomin Jeong, ChiHye Chung, Gianluca Cestra e Sunghoe Chang. "nArgBP2 regulates excitatory synapse formation by controlling dendritic spine morphology". Proceedings of the National Academy of Sciences 113, n. 24 (25 maggio 2016): 6749–54. http://dx.doi.org/10.1073/pnas.1600944113.
Testo completoAbstract (sommario):
Neural Abelson-related gene-binding protein 2 (nArgBP2) was originally identified as a protein that directly interacts with synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3), a postsynaptic scaffolding protein critical for the assembly of glutamatergic synapses. Although genetic deletion of nArgBP2 in mice leads to manic/bipolar-like behaviors resembling many aspects of symptoms in patients with bipolar disorder, the actual function of nArgBP2 at the synapse is completely unknown. Here, we found that the knockdown (KD) of nArgBP2 by specific small hairpin RNAs (shRNAs) resulted in a dramatic change in dendritic spine morphology. Reintroducing shRNA-resistant nArgBP2 reversed these defects. In particular, nArgBP2 KD impaired spine-synapse formation such that excitatory synapses terminated mostly at dendritic shafts instead of spine heads in spiny neurons, although inhibitory synapse formation was not affected. nArgBP2 KD further caused a marked increase of actin cytoskeleton dynamics in spines, which was associated with increased Wiskott–Aldrich syndrome protein-family verprolin homologous protein 1 (WAVE1)/p21-activated kinase (PAK) phosphorylation and reduced activity of cofilin. These effects of nArgBP2 KD in spines were rescued by inhibiting PAK or activating cofilin combined with sequestration of WAVE. Together, our results suggest that nArgBP2 functions to regulate spine morphogenesis and subsequent spine-synapse formation at glutamatergic synapses. They also raise the possibility that the aberrant regulation of synaptic actin filaments caused by reduced nArgBP2 expression may contribute to the manifestation of the synaptic dysfunction observed in manic/bipolar disorder.
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Kawasaki, Fumiko, e Richard W. Ordway. "The Drosophila NSF Protein, dNSF1, Plays a Similar Role at Neuromuscular and Some Central Synapses". Journal of Neurophysiology 82, n. 1 (1 luglio 1999): 123–30. http://dx.doi.org/10.1152/jn.1999.82.1.123.
Testo completoAbstract (sommario):
The N-ethylmaleimide sensitive fusion protein (NSF) was originally identified as a cytosolic factor required for constitutive vesicular transport and later implicated in synaptic vesicle trafficking as well. Our previous work at neuromuscular synapses in the temperature-sensitive NSF mutant, comatose( comt), has shown that the comtgene product, dNSF1, functions after synaptic vesicle docking in the priming of vesicles for fast calcium-triggered fusion. Here we investigate whether dNSF1 performs a similar function at central synapses associated with the well-characterized giant fiber neural pathway. These include a synapse within the giant fiber pathway, made by the peripherally synapsing interneuron (PSI), as well as synapses providing input to the giant fiber pathway. The latency (delay) between stimulation and a resulting muscle action potential was used to assess the function of each class of synapses. Repetitive stimulation of the giant fiber pathway in comt produced wild-type responses at both 20 and 36°C, exhibiting a characteristic and constant latency between stimulation and the muscle response. In contrast, stimulation of presynaptic inputs to the giant fiber (referred to as the “long latency pathway”) revealed a striking difference between wild type and comt at 36°C. Repetitive stimulation of the long latency pathway led to a progressive, activity-dependent increase in the response latency in comt, but not in wild type. Thus the giant fiber pathway, including the PSI synapse, appears to function normally in comt, whereas the presynaptic inputs to the giant fiber pathway are disrupted. Several aspects of the progressive latency increase observed in the long latency pathway can be understood in the context of the activity-dependent reduction in neurotransmitter release we observed previously at neuromuscular synapses. These results suggest that repetitive stimulation causes a progressive reduction in neurotransmitter release by presynaptic inputs to the giant fiber neuron, resulting in an increased latency preceding a giant fiber action potential. Thus synapses presynaptic to the giant fiber appear to utilize dNSF1 in a manner similar to the neuromuscular synapse, whereas the PSI chemical synapse may differ with respect to the expression or activity of dNSF1.
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Rosenthal, Justin S., Jun Yin, Jingce Lei, Anupama Sathyamurthy, Jacob Short, Caixia Long, Emma Spillman, Chengyu Sheng e Quan Yuan. "Temporal regulation of nicotinic acetylcholine receptor subunits supports central cholinergic synapse development in Drosophila". Proceedings of the National Academy of Sciences 118, n. 23 (1 giugno 2021): e2004685118. http://dx.doi.org/10.1073/pnas.2004685118.
Testo completoAbstract (sommario):
The construction and maturation of the postsynaptic apparatus are crucial for synapse and dendrite development. The fundamental mechanisms underlying these processes are most often studied in glutamatergic central synapses in vertebrates. Whether the same principles apply to excitatory cholinergic synapses, such as those found in the insect central nervous system, is not known. To address this question, we investigated a group of projection neurons in the Drosophila larval visual system, the ventral lateral neurons (LNvs), and identified nAchRα1 (Dα1) and nAchRα6 (Dα6) as the main functional nicotinic acetylcholine receptor (nAchR) subunits in the larval LNvs. Using morphological analyses and calcium imaging studies, we demonstrated critical roles of these two subunits in supporting dendrite morphogenesis and synaptic transmission. Furthermore, our RNA sequencing analyses and endogenous tagging approach identified distinct transcriptional controls over the two subunits in the LNvs, which led to the up-regulation of Dα1 and down-regulation of Dα6 during larval development as well as to an activity-dependent suppression of Dα1. Additional functional analyses of synapse formation and dendrite dynamics further revealed a close association between the temporal regulation of individual nAchR subunits and their sequential requirements during the cholinergic synapse maturation. Together, our findings support transcriptional control of nAchR subunits as a core element of developmental and activity-dependent regulation of central cholinergic synapses.
26
VERZI, D. "Modeling activity-dependent synapse restructuring". Bulletin of Mathematical Biology 66, n. 4 (luglio 2004): 745–62. http://dx.doi.org/10.1016/j.bulm.2003.10.005.
Testo completo
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Hickmott, Peter W., e Martha Constantine-Paton. "Experimental Down-Regulation of the NMDA Channel Associated With Synapse Pruning". Journal of Neurophysiology 78, n. 2 (1 agosto 1997): 1096–107. http://dx.doi.org/10.1152/jn.1997.78.2.1096.
Testo completoAbstract (sommario):
Hickmott, Peter W. and Martha Constantine-Paton. Experimental down-regulation of the NMDA channel associated with synapse pruning. J. Neurophysiol. 78: 1096–1107, 1997. The N-methyl-d-aspartate (NMDA) receptor has been implicated in activity-dependent synapse stabilization, but its role as a detector of correlated activity during development is debated. In the amphibian retinotectal system, synaptic sorting and stabilization occur throughout larval life, and map refinement is dependent on continuous NMDA receptor function. Moreover, tadpole tecta chronically treated with NMDA selectively fail to maintain retinal synapses wherever their activity correlations are lowest. To determine whether this synapse elimination is associated with a specific down-regulation of NMDA receptor function, whole cell voltage-clamp recordings were made from single neurons in tectal slices. After chronic NMDA treatment, decreases in the magnitude of NMDA currents were detected in glutamatergic synaptic currents, in agonist-evoked currents, and in single-channel currents activated by NMDA. The results suggest that the efficacy of NMDA receptors on tectal neurons determines the amount of correlation required to stabilize sets of tectal inputs during formation of the retinotectal projection.
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Hardingham, Neil R., Giles E. Hardingham, Kevin D. Fox e Julian J. B. Jack. "Presynaptic Efficacy Directs Normalization of Synaptic Strength in Layer 2/3 Rat Neocortex After Paired Activity". Journal of Neurophysiology 97, n. 4 (aprile 2007): 2965–75. http://dx.doi.org/10.1152/jn.01352.2006.
Testo completoAbstract (sommario):
Paired neuronal activity is known to induce changes in synaptic strength that result in the synapse in question having different properties to unmodified synapses. Here we show that in layer 2/3 excitatory connections in young adult rat cortex paired activity acts to normalize the strength and quantal parameters of connections. Paired action potential firing produces long-term potentiation in only a third of connections, whereas a third remain with their amplitude unchanged and a third exhibit long-term depression. Furthermore, the direction of plasticity can be predicted by the initial strength of the connection: weak connections potentiate and strong connections depress. A quantal analysis reveals that changes in synaptic efficacy were predominantly presynaptic in locus and that the key determinant of the direction and magnitude of synaptic modification was the initial release probability ( Pr) of the synapse, which correlated inversely with change in Pr after pairing. Furthermore, distal synapses also exhibited larger potentiations including postsynaptic increases in efficacy, whereas more proximal inputs did not. This may represent a means by which distal synapses preferentially increase their efficacy to achieve equal weighting at the soma. Paired activity thus acts to normalize synaptic strength, by both pre- and postsynaptic mechanisms.
29
Kano, Masanobu, e Takaki Watanabe. "Developmental synapse remodeling in the cerebellum and visual thalamus". F1000Research 8 (25 luglio 2019): 1191. http://dx.doi.org/10.12688/f1000research.18903.1.
Testo completoAbstract (sommario):
Functional neural circuits of mature animals are shaped during postnatal development by eliminating early-formed redundant synapses and strengthening of necessary connections. In the nervous system of newborn animals, redundant synapses are only transient features of the circuit. During subsequent postnatal development, some synapses are strengthened whereas other redundant connections are weakened and eventually eliminated. In this review, we introduce recent studies on the mechanisms of developmental remodeling of climbing fiber–to–Purkinje cell synapses in the cerebellum and synapses from the retina to neurons in the dorsal lateral geniculate nucleus of the visual thalamus (retinogeniculate synapses). These are the two representative models of developmental synapse remodeling in the brain and they share basic principles, including dependency on neural activity. However, recent studies have disclosed that, in several respects, the two models use different molecules and strategies to establish mature synaptic connectivity. We describe similarities and differences between the two models and discuss remaining issues to be tackled in the future in order to understand the general schemes of developmental synapse remodeling.
30
Chubykin, Alexander A., Xinran Liu, Davide Comoletti, Igor Tsigelny, Palmer Taylor e Thomas C. Südhof. "Dissection of Synapse Induction by Neuroligins". Journal of Biological Chemistry 280, n. 23 (29 marzo 2005): 22365–74. http://dx.doi.org/10.1074/jbc.m410723200.
Testo completoAbstract (sommario):
To study synapse formation by neuroligins, we co-cultured hippocampal neurons with COS cells expressing wild type and mutant neuroligins. The large size of COS cells makes it possible to test the effect of neuroligins presented over an extended surface area. We found that a uniform lawn of wild type neuroligins displayed on the cell surface triggers the formation of hundreds of uniformly sized, individual synaptic contacts that are labeled with neurexin antibodies. Electron microscopy revealed that these artificial synapses contain a presynaptic active zone with docked vesicles and often feature a postsynaptic density. Neuroligins 1, 2, and 3 were active in this assay. Mutations in two surface loops of neuroligin 1 abolished neuroligin binding to neurexin 1β, a presumptive presynaptic binding partner for postsynaptic neuroligins, and blocked synapse formation. An analysis of mutant neuroligins with an amino acid substitution that corresponds to a mutation described in patients with an autistic syndrome confirmed previous reports that these mutant neuroligins have a compromised capacity to be transported to the cell surface. Nevertheless, the small percentage of mutant neuroligins that reached the cell surface still induced synapse formation. Viewed together, our data suggest that neuroligins generally promote artificial synapse formation in a manner that is associated with β-neurexin binding and results in morphologically well differentiated synapses and that a neuroligin mutation found in autism spectrum disorders impairs cell-surface transport but does not completely abolish synapse formation activity.
31
Salmasi, Mehrdad, Martin Stemmler, Stefan Glasauer e Alex Loebel. "Synaptic Information Transmission in a Two-State Model of Short-Term Facilitation". Entropy 21, n. 8 (2 agosto 2019): 756. http://dx.doi.org/10.3390/e21080756.
Testo completoAbstract (sommario):
Action potentials (spikes) can trigger the release of a neurotransmitter at chemical synapses between neurons. Such release is uncertain, as it occurs only with a certain probability. Moreover, synaptic release can occur independently of an action potential (asynchronous release) and depends on the history of synaptic activity. We focus here on short-term synaptic facilitation, in which a sequence of action potentials can temporarily increase the release probability of the synapse. In contrast to the phenomenon of short-term depression, quantifying the information transmission in facilitating synapses remains to be done. We find rigorous lower and upper bounds for the rate of information transmission in a model of synaptic facilitation. We treat the synapse as a two-state binary asymmetric channel, in which the arrival of an action potential shifts the synapse to a facilitated state, while in the absence of a spike, the synapse returns to its baseline state. The information bounds are functions of both the asynchronous and synchronous release parameters. If synchronous release facilitates more than asynchronous release, the mutual information rate increases. In contrast, short-term facilitation degrades information transmission when the synchronous release probability is intrinsically high. As synaptic release is energetically expensive, we exploit the information bounds to determine the energy–information trade-off in facilitating synapses. We show that unlike information rate, the energy-normalized information rate is robust with respect to variations in the strength of facilitation.
32
Li, Yan, Jonathan Popko, Kelly A. Krogh e Stanley A. Thayer. "Epileptiform stimulus increases Homer 1a expression to modulate synapse number and activity in hippocampal cultures". Journal of Neurophysiology 109, n. 6 (15 marzo 2013): 1494–504. http://dx.doi.org/10.1152/jn.00580.2012.
Testo completoAbstract (sommario):
Neurons adapt to seizure activity structurally and functionally to attenuate hyperactive neural circuits. Homer proteins provide a scaffold in the postsynaptic density (PSD) by binding to ligands through an EVH1 domain and to other Homer proteins by a coiled-coil domain. The short Homer isoform 1a (H1a) has a ligand-binding domain but lacks a coiled-coil domain and thus acts in a dominant-negative manner to uncouple Homer scaffolds. Here, we show that treating rat hippocampal cultures with bicuculline and 4-aminopyridine (Bic+4-AP) evoked epileptiform activity and synchronized Ca2+ spiking, measured with whole cell current-clamp and fura-2-based digital imaging; Bic+4-AP increased H1a mRNA through the activation of metabotropic glutamate receptor 5 (mGluR5). Treatment with Bic+4-AP for 4 h attenuated burst firing and induced synapse loss. Synaptic changes were measured using a confocal imaging-based assay that quantified clusters of PSD-95 fused to green fluorescent protein. Treatment with an mGluR5 antagonist blocked H1a expression, synapse loss, and burst attenuation. Overexpression of H1a inhibited burst firing similar to Bic+4-AP treatment. Furthermore, knockdown of H1a using a short hairpin RNA (shRNA) strategy reduced synapse loss and burst attenuation induced by Bic+4-AP treatment. Thus an epileptiform stimulus applied to hippocampal neurons in culture induced burst firing and H1a expression through the activation of mGluR5; a 4-h exposure to this stimulus resulted in synapse loss and burst attenuation. These results suggest that H1a expression functions in a negative-feedback manner to reduce network excitability by regulating the number of synapses.
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Fedorovich, Sergei V., e Tatyana V. Waseem. "Metabolic regulation of synaptic activity". Reviews in the Neurosciences 29, n. 8 (27 novembre 2018): 825–35. http://dx.doi.org/10.1515/revneuro-2017-0090.
Testo completoAbstract (sommario):
AbstractBrain tissue is bioenergetically expensive. In humans, it composes approximately 2% of body weight and accounts for approximately 20% of calorie consumption. The brain consumes energy mostly for ion and neurotransmitter transport, a process that occurs primarily in synapses. Therefore, synapses are expensive for any living creature who has brain. In many brain diseases, synapses are damaged earlier than neurons start dying. Synapses may be considered as vulnerable sites on a neuron. Ischemic stroke, an acute disturbance of blood flow in the brain, is an example of a metabolic disease that affects synapses. The associated excessive glutamate release, called excitotoxicity, is involved in neuronal death in brain ischemia. Another example of a metabolic disease is hypoglycemia, a complication of diabetes mellitus, which leads to neuronal death and brain dysfunction. However, synapse function can be corrected with “bioenergetic medicine”. In this review, a ketogenic diet is discussed as a curative option. In support of a ketogenic diet, whereby carbohydrates are replaced for fats in daily meals, epileptic seizures can be terminated. In this review, we discuss possible metabolic sensors in synapses. These may include molecules that perceive changes in composition of extracellular space, for instance, ketone body and lactate receptors, or molecules reacting to changes in cytosol, for instance, KATPchannels or AMP kinase. Inhibition of endocytosis is believed to be a universal synaptic mechanism of adaptation to metabolic changes.
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Bamji, Shernaz X., Beatriz Rico, Nikole Kimes e Louis F. Reichardt. "BDNF mobilizes synaptic vesicles and enhances synapse formation by disrupting cadherin–β-catenin interactions". Journal of Cell Biology 174, n. 2 (10 luglio 2006): 289–99. http://dx.doi.org/10.1083/jcb.200601087.
Testo completoAbstract (sommario):
Neurons of the vertebrate central nervous system have the capacity to modify synapse number, morphology, and efficacy in response to activity. Some of these functions can be attributed to activity-induced synthesis and secretion of the neurotrophin brain-derived neurotrophic factor (BDNF); however, the molecular mechanisms by which BDNF mediates these events are still not well understood. Using time-lapse confocal analysis, we show that BDNF mobilizes synaptic vesicles at existing synapses, resulting in small clusters of synaptic vesicles “splitting” away from synaptic sites. We demonstrate that BDNF's ability to mobilize synaptic vesicle clusters depends on the dissociation of cadherin–β-catenin adhesion complexes that occurs after tyrosine phosphorylation of β-catenin. Artificially maintaining cadherin–β-catenin complexes in the presence of BDNF abolishes the BDNF-mediated enhancement of synaptic vesicle mobility, as well as the longer-term BDNF-mediated increase in synapse number. Together, this data demonstrates that the disruption of cadherin–β-catenin complexes is an important molecular event through which BDNF increases synapse density in cultured hippocampal neurons.
35
TSODYKS, M. V. "ASSOCIATIVE MEMORY IN NEURAL NETWORKS WITH THE HEBBIAN LEARNING RULE". Modern Physics Letters B 03, n. 07 (10 maggio 1989): 555–60. http://dx.doi.org/10.1142/s021798498900087x.
Testo completoAbstract (sommario):
We consider the Hopfield model with the most simple form of the Hebbian learning rule, when only simultaneous activity of pre- and post-synaptic neurons leads to modification of synapse. An extra inhibition proportional to full network activity is needed. Both symmetric nondiluted and asymmetric diluted networks are considered. The model performs well at extremely low level of activity p<K−1/2, where K is the mean number of synapses per neuron.
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Gardner, D. "Sets of synaptic currents paired by common presynaptic or postsynaptic neurons". Journal of Neurophysiology 61, n. 4 (1 aprile 1989): 845–53. http://dx.doi.org/10.1152/jn.1989.61.4.845.
Testo completoAbstract (sommario):
1. In the buccal ganglia of Aplysia, presynaptic neurons B4 and B5 produce similar inhibitory postsynaptic currents (PSCs) in several postsynaptic follower cells. Previous work has shown that both duration and amplitude of these PSCs vary, that each parameter may be altered transiently by manipulating presynaptic activity, and that these variations affect synaptic efficacy. 2. To permit synapse-to-synapse comparisons, the mean and coefficient of variation (CV) of both peak conductance (gpeak) and time constant of decay (tau) were determined for sets of synaptic currents evoked by direct intracellular stimulation of presynaptic neurons. For 56 synapses, gpeak = 0.40 +/- 0.33 (SD) microS for a CV of 0.83, and tau = 19.7 +/- 4.0 ms for a CV of 0.20. The synapse-to-synapse variability was within 5% of values obtained from a previous population. 3. The relative contributions of presynaptic and postsynaptic factors to efficacy and variability of PSCs were examined by recordings from two classes of three-cell networks and by comparing values of gpeak and tau at synapses sharing a common presynaptic or postsynaptic neuron. 4. In the first case, paired presynaptic inputs from B4 and B5 converged on a common postsynaptic cell. For 16 examples of this case, mean values of both gpeak and tau recorded in a single follower cell, but produced by different presynaptic neurons, were significantly closer than those recorded in different followers (P less than 0.001). The common postsynaptic cell did not constrain variability of these parameters; CVs for paired synapses were not significantly different from the population (P greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)
37
Round, June L., Tamar Tomassian, Min Zhang, Viresh Patel, Stephen P. Schoenberger e M. Carrie Miceli. "Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells". Journal of Experimental Medicine 201, n. 3 (7 febbraio 2005): 419–30. http://dx.doi.org/10.1084/jem.20041428.
Testo completoAbstract (sommario):
Lipid raft membrane compartmentalization and membrane-associated guanylate kinase (MAGUK) family molecular scaffolds function in establishing cell polarity and organizing signal transducers within epithelial cell junctions and neuronal synapses. Here, we elucidate a role for the MAGUK protein, Dlgh1, in polarized T cell synapse assembly and T cell function. We find that Dlgh1 translocates to the immune synapse and lipid rafts in response to T cell receptor (TCR)/CD28 engagement and that LckSH3-mediated interactions with Dlgh1 control its membrane targeting. TCR/CD28 engagement induces the formation of endogenous Lck–Dlgh1–Zap70–Wiskott-Aldrich syndrome protein (WASp) complexes in which Dlgh1 acts to facilitate interactions of Lck with Zap70 and WASp. Using small interfering RNA and overexpression approaches, we show that Dlgh1 promotes antigen-induced actin polymerization, synaptic raft and TCR clustering, nuclear factor of activated T cell activity, and cytokine production. We propose that Dlgh1 coordinates TCR/CD28-induced actin-driven T cell synapse assembly, signal transduction, and effector function. These findings highlight common molecular strategies used to regulate cell polarity, synapse assembly, and transducer organization in diverse cellular systems.
38
Fuhrmann, Galit, Idan Segev, Henry Markram e Misha Tsodyks. "Coding of Temporal Information by Activity-Dependent Synapses". Journal of Neurophysiology 87, n. 1 (1 gennaio 2002): 140–48. http://dx.doi.org/10.1152/jn.00258.2001.
Testo completoAbstract (sommario):
Synaptic transmission in the neocortex is dynamic, such that the magnitude of the postsynaptic response changes with the history of the presynaptic activity. Therefore each response carries information about the temporal structure of the preceding presynaptic input spike train. We quantitatively analyze the information about previous interspike intervals, contained in single responses of dynamic synapses, using methods from information theory applied to experimentally based deterministic and probabilistic phenomenological models of depressing and facilitating synapses. We show that for any given dynamic synapse, there exists an optimal frequency of presynaptic spike firing for which the information content is maximal; simple relations between this optimal frequency and the synaptic parameters are derived. Depressing neocortical synapses are optimized for coding temporal information at low firing rates of 0.5–5 Hz, typical to the spontaneous activity of cortical neurons, and carry significant information about the timing of up to four preceding presynaptic spikes. Facilitating synapses, however, are optimized to code information at higher presynaptic rates of 9–70 Hz and can represent the timing of over eight presynaptic spikes.
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Jin, Hui, Vincent Guacci e Hong-Guo Yu. "Pds5 is required for homologue pairing and inhibits synapsis of sister chromatids during yeast meiosis". Journal of Cell Biology 186, n. 5 (7 settembre 2009): 713–25. http://dx.doi.org/10.1083/jcb.200810107.
Testo completoAbstract (sommario):
During meiosis, homologues become juxtaposed and synapsed along their entire length. Mutations in the cohesin complex disrupt not only sister chromatid cohesion but also homologue pairing and synaptonemal complex formation. In this study, we report that Pds5, a cohesin-associated protein known to regulate sister chromatid cohesion, is required for homologue pairing and synapsis in budding yeast. Pds5 colocalizes with cohesin along the length of meiotic chromosomes. In the absence of Pds5, the meiotic cohesin subunit Rec8 remains bound to chromosomes with only minor defects in sister chromatid cohesion, but sister chromatids synapse instead of homologues. Double-strand breaks (DSBs) are formed but are not repaired efficiently. In addition, meiotic chromosomes undergo hypercondensation. When the mitotic cohesin subunit Mcd1 is substituted for Rec8 in Pds5-depleted cells, chromosomes still hypercondense, but synapsis of sister chromatids is abolished. These data suggest that Pds5 modulates the Rec8 activity to facilitate chromosome morphological changes required for homologue synapsis, DSB repair, and meiotic chromosome segregation.
40
Lim, Agnes Fang Yi, Wei Lee Lim e Toh Hean Ch’ng. "Activity-dependent synapse to nucleus signaling". Neurobiology of Learning and Memory 138 (febbraio 2017): 78–84. http://dx.doi.org/10.1016/j.nlm.2016.07.024.
Testo completo
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Buffelli, Mario, Giuseppe Busetto, Carlo Bidoia, Morgana Favero e Alberto Cangiano. "Activity-Dependent Synaptic Competition at Mammalian Neuromuscular Junctions". Physiology 19, n. 3 (giugno 2004): 85–91. http://dx.doi.org/10.1152/nips.01464.2003.
Testo completoAbstract (sommario):
Synapse elimination is a widespread developmental process in the peripheral and central nervous system that brings about refinement of neural connections through epigenetic mechanisms. Here we describe recent advances concerning the role of the pattern of motoneuronal firing, synchronous or asynchronous, in neuromuscular synapse elimination.
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Sjöström, P. Jesper, Ede A. Rancz, Arnd Roth e Michael Häusser. "Dendritic Excitability and Synaptic Plasticity". Physiological Reviews 88, n. 2 (aprile 2008): 769–840. http://dx.doi.org/10.1152/physrev.00016.2007.
Testo completoAbstract (sommario):
Most synaptic inputs are made onto the dendritic tree. Recent work has shown that dendrites play an active role in transforming synaptic input into neuronal output and in defining the relationships between active synapses. In this review, we discuss how these dendritic properties influence the rules governing the induction of synaptic plasticity. We argue that the location of synapses in the dendritic tree, and the type of dendritic excitability associated with each synapse, play decisive roles in determining the plastic properties of that synapse. Furthermore, since the electrical properties of the dendritic tree are not static, but can be altered by neuromodulators and by synaptic activity itself, we discuss how learning rules may be dynamically shaped by tuning dendritic function. We conclude by describing how this reciprocal relationship between plasticity of dendritic excitability and synaptic plasticity has changed our view of information processing and memory storage in neuronal networks.
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Hu, Wei, Chenyi An e Wei J. Chen. "Molecular Mechanoneurobiology: An Emerging Angle to Explore Neural Synaptic Functions". BioMed Research International 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/486827.
Testo completoAbstract (sommario):
Neural synapses are intercellular asymmetrical junctions that transmit biochemical and biophysical information between a neuron and a target cell. They are very tight, dynamic, and well organized by many synaptic adhesion molecules, signaling receptors, ion channels, and their associated cytoskeleton that bear forces. Mechanical forces have been an emerging factor in regulating axon guidance and growth, synapse formation and plasticity in physiological and pathological brain activity. Therefore, mechanical forces are undoubtedly exerted on those synaptic molecules and modulate their functions. Here we review current progress on how mechanical forces regulate receptor-ligand interactions, protein conformations, ion channels activation, and cytoskeleton dynamics and discuss how these regulations potentially affect synapse formation, stabilization, and plasticity.
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Bernardinelli, Yann, Dominique Muller e Irina Nikonenko. "Astrocyte-Synapse Structural Plasticity". Neural Plasticity 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/232105.
Testo completoAbstract (sommario):
The function and efficacy of synaptic transmission are determined not only by the composition and activity of pre- and postsynaptic components but also by the environment in which a synapse is embedded. Glial cells constitute an important part of this environment and participate in several aspects of synaptic functions. Among the glial cell family, the roles played by astrocytes at the synaptic level are particularly important, ranging from the trophic support to the fine-tuning of transmission. Astrocytic structures are frequently observed in close association with glutamatergic synapses, providing a morphological entity for bidirectional interactions with synapses. Experimental evidence indicates that astrocytes sense neuronal activity by elevating their intracellular calcium in response to neurotransmitters and may communicate with neurons. The precise role of astrocytes in regulating synaptic properties, function, and plasticity remains however a subject of intense debate and many aspects of their interactions with neurons remain to be investigated. A particularly intriguing aspect is their ability to rapidly restructure their processes and modify their coverage of the synaptic elements. The present review summarizes some of these findings with a particular focus on the mechanisms driving this form of structural plasticity and its possible impact on synaptic structure and function.
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Huang, Huiqian, Xiaochen Lin, Zhuoyi Liang, Teng Zhao, Shengwang Du, Michael M. T. Loy, Kwok-On Lai, Amy K. Y. Fu e Nancy Y. Ip. "Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development". Proceedings of the National Academy of Sciences 114, n. 33 (31 luglio 2017): E6992—E7001. http://dx.doi.org/10.1073/pnas.1708240114.
Testo completoAbstract (sommario):
The experience-dependent modulation of brain circuitry depends on dynamic changes in synaptic connections that are guided by neuronal activity. In particular, postsynaptic maturation requires changes in dendritic spine morphology, the targeting of postsynaptic proteins, and the insertion of synaptic neurotransmitter receptors. Thus, it is critical to understand how neuronal activity controls postsynaptic maturation. Here we report that the scaffold protein liprinα1 and its phosphorylation by cyclin-dependent kinase 5 (Cdk5) are critical for the maturation of excitatory synapses through regulation of the synaptic localization of the major postsynaptic organizer postsynaptic density (PSD)-95. Whereas Cdk5 phosphorylates liprinα1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprinα1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprinα1 phosphorylation increases the colocalization of liprinα1 with PSD-95. Furthermore, disruption of liprinα1 phosphorylation by a small interfering peptide, siLIP, promotes the synaptic localization of PSD-95 and enhances synaptic strength in vivo. Our findings collectively demonstrate that the Cdk5-dependent phosphorylation of liprinα1 is important for the postsynaptic organization during activity-dependent synapse development.
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Jasinska, Malgorzata, Anna Grzegorczyk, Ewa Jasek, Jan Litwin, Malgorzata Kossut, Grazyna Barbacka-Surowiak e Elzbieta Pyza. "Daily rhythm of synapse turnover in mouse somatosensory cortex". Acta Neurobiologiae Experimentalis 74, n. 1 (31 marzo 2014): 104–10. http://dx.doi.org/10.55782/ane-2014-1977.
Testo completoAbstract (sommario):
The whisker representations in the somatosensory barrel cortex of mice are modulated by sensory inputs associated with animal motor behavior which shows circadian rhythmicity. In a C57/BL mouse strain kept under a light/dark (LD 12:12) regime, we observed daily structural changes in the barrel cortex, correlated with the locomotor activity level. Stereological analysis of serial electron microscopic sections of the barrel cortex of mice sacrificed during their active or rest period, revealed an increase in the total numerical density of synapses and in the density of excitatory synapses located on dendritic spines during the rest, as well as an increase in the density of inhibitory synapses located on double-synapse spines during the active period. This is the first report demonstrating a daily rhythm in remodeling of the mammalian somatosensory cortex, manifested by changes in the density of synapses and dendritic spines. Moreover, we have found that the excitatory and inhibitory synapses are differently regulated during the day/night cycle.
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Tamzalit, Fella, Mitchell S. Wang, Weiyang Jin, Maria Tello-Lafoz, Vitaly Boyko, John M. Heddleston, Charles T. Black, Lance C. Kam e Morgan Huse. "Interfacial actin protrusions mechanically enhance killing by cytotoxic T cells". Science Immunology 4, n. 33 (22 marzo 2019): eaav5445. http://dx.doi.org/10.1126/sciimmunol.aav5445.
Testo completoAbstract (sommario):
Cytotoxic T lymphocytes (CTLs) kill by forming immunological synapses with target cells and secreting toxic proteases and the pore-forming protein perforin into the intercellular space. Immunological synapses are highly dynamic structures that boost perforin activity by applying mechanical force against the target cell. Here, we used high-resolution imaging and microfabrication to investigate how CTLs exert synaptic forces and coordinate their mechanical output with perforin secretion. Using micropatterned stimulatory substrates that enable synapse growth in three dimensions, we found that perforin release occurs at the base of actin-rich protrusions that extend from central and intermediate locations within the synapse. These protrusions, which depended on the cytoskeletal regulator WASP and the Arp2/3 actin nucleation complex, were required for synaptic force exertion and efficient killing. They also mediated physical deformation of the target cell surface during CTL–target cell interactions. Our results reveal the mechanical basis of cellular cytotoxicity and highlight the functional importance of dynamic, three-dimensional architecture in immune cell-cell interfaces.
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Rowley, Paul A., e Margaret C. M. Smith. "Role of the N-Terminal Domain of φC31 Integrase in attB-attP Synapsis". Journal of Bacteriology 190, n. 20 (8 agosto 2008): 6918–21. http://dx.doi.org/10.1128/jb.00612-08.
Testo completoAbstract (sommario):
ABSTRACT φC31 integrase is a serine recombinase containing an N-terminal domain (NTD) that provides catalytic activity and a large C-terminal domain that controls which pair of DNA substrates is able to synapse. We show here that substitutions in amino acid V129 in the NTD can lead to defects in synapsis and DNA cleavage, indicating that the NTD also has an important role in synapsis.
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Hedrick, Nathan G., William J. Wright e Takaki Komiyama. "Local and global predictors of synapse elimination during motor learning". Science Advances 10, n. 11 (15 marzo 2024). http://dx.doi.org/10.1126/sciadv.adk0540.
Testo completoAbstract (sommario):
During learning, synaptic connections between excitatory neurons in the brain display considerable dynamism, with new connections being added and old connections eliminated. Synapse elimination offers an opportunity to understand the features of synapses that the brain deems dispensable. However, with limited observations of synaptic activity and plasticity in vivo, the features of synapses subjected to elimination remain poorly understood. Here, we examined the functional basis of synapse elimination in the apical dendrites of L2/3 neurons in the primary motor cortex throughout motor learning. We found no evidence that synapse elimination is facilitated by a lack of activity or other local forms of plasticity. Instead, eliminated synapses display asynchronous activity with nearby synapses, suggesting that functional synaptic clustering is a critical component of synapse survival. In addition, eliminated synapses show delayed activity timing with respect to postsynaptic output. Thus, synaptic inputs that fail to be co-active with their neighboring synapses or are mistimed with neuronal output are targeted for elimination.
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Teo, Samuel, e Patricia C. Salinas. "Wnt-Frizzled Signaling Regulates Activity-Mediated Synapse Formation". Frontiers in Molecular Neuroscience 14 (14 giugno 2021). http://dx.doi.org/10.3389/fnmol.2021.683035.
Testo completoAbstract (sommario):
The formation of synapses is a tightly regulated process that requires the coordinated assembly of the presynaptic and postsynaptic sides. Defects in synaptogenesis during development or in the adult can lead to neurodevelopmental disorders, neurological disorders, and neurodegenerative diseases. In order to develop therapeutic approaches for these neurological conditions, we must first understand the molecular mechanisms that regulate synapse formation. The Wnt family of secreted glycoproteins are key regulators of synapse formation in different model systems from invertebrates to mammals. In this review, we will discuss the role of Wnt signaling in the formation of excitatory synapses in the mammalian brain by focusing on Wnt7a and Wnt5a, two Wnt ligands that play an in vivo role in this process. We will also discuss how changes in neuronal activity modulate the expression and/or release of Wnts, resulting in changes in the localization of surface levels of Frizzled, key Wnt receptors, at the synapse. Thus, changes in neuronal activity influence the magnitude of Wnt signaling, which in turn contributes to activity-mediated synapse formation.