Journal articles: 'Synaptic turnover'

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Zimmermann, H., W. Volknandt, B. Wittich, and A. Hausinger. "Synaptic vesicle life cycle and synaptic turnover." Journal of Physiology-Paris 87, no. 3 (January 1993): 159–70. http://dx.doi.org/10.1016/0928-4257(93)90027-q.

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Jones, Rachel. "Kinetics of Synaptic Protein Turnover Regulate Synaptic Size." PLoS Biology 4, no. 11 (November 7, 2006): e404. http://dx.doi.org/10.1371/journal.pbio.0040404.

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Nabavi, Melinda, and P. Robin Hiesinger. "Turnover of synaptic adhesion molecules." Molecular and Cellular Neuroscience 124 (March 2023): 103816. http://dx.doi.org/10.1016/j.mcn.2023.103816.

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Alvarez-Castelao, Beatriz, and Erin M. Schuman. "The Regulation of Synaptic Protein Turnover." Journal of Biological Chemistry 290, no. 48 (October 9, 2015): 28623–30. http://dx.doi.org/10.1074/jbc.r115.657130.

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Murphy, T. H., D. D. Wright, and J. M. Baraban. "Phosphoinositide Turnover Associated with Synaptic Transmission." Journal of Neurochemistry 59, no. 6 (October 5, 2006): 2336–39. http://dx.doi.org/10.1111/j.1471-4159.1992.tb10130.x.

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Schaefers, Andrea T. U., Keren Grafen, Gertraud Teuchert-Noodt, and York Winter. "Synaptic Remodeling in the Dentate Gyrus, CA3, CA1, Subiculum, and Entorhinal Cortex of Mice: Effects of Deprived Rearing and Voluntary Running." Neural Plasticity 2010 (2010): 1–11. http://dx.doi.org/10.1155/2010/870573.

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Hippocampal cell proliferation is strongly increased and synaptic turnover decreased after rearing under social and physical deprivation in gerbils (Meriones unguiculatus). We examined if a similar epigenetic effect of rearing environment on adult neuroplastic responses can be found in mice (Mus musculus). We examined synaptic turnover rates in the dentate gyrus, CA3, CA1, subiculum, and entorhinal cortex. No direct effects of deprived rearing on rates of synaptic turnover were found in any of the studied regions. However, adult wheel running had the effect of leveling layer-specific differences in synaptic remodeling in the dentate gyrus, CA3, and CA1, but not in the entorhinal cortex and subiculum of animals of both rearing treatments. Epigenetic effects during juvenile development affected adult neural plasticity in mice, but seemed to be less pronounced than in gerbils.

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Tao-Cheng, J. H., A. Dosemeci, P. E. Gallant, S. Miller, J. A. Galbraith, C. A. Winters, R. Azzam, and T. S. Reese. "Rapid turnover of spinules at synaptic terminals." Neuroscience 160, no. 1 (April 2009): 42–50. http://dx.doi.org/10.1016/j.neuroscience.2009.02.031.

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Nath, Arup R., Ileea Larente, Taufik Valiante, and Elise F. Stanley. "Synaptic Vesicle Turnover in Human Brain Synaptosomes." Biophysical Journal 108, no. 2 (January 2015): 100a. http://dx.doi.org/10.1016/j.bpj.2014.11.575.

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Cohen, Laurie D., Rina Zuchman, Oksana Sorokina, Anke Müller, Daniela C. Dieterich, J. Douglas Armstrong, Tamar Ziv, and Noam E. Ziv. "Metabolic Turnover of Synaptic Proteins: Kinetics, Interdependencies and Implications for Synaptic Maintenance." PLoS ONE 8, no. 5 (May 2, 2013): e63191. http://dx.doi.org/10.1371/journal.pone.0063191.

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Lin, Amy W., and Heng-Ye Man. "Ubiquitination of Neurotransmitter Receptors and Postsynaptic Scaffolding Proteins." Neural Plasticity 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/432057.

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The human brain is made up of an extensive network of neurons that communicate by forming specialized connections called synapses. The amount, location, and dynamic turnover of synaptic proteins, including neurotransmitter receptors and synaptic scaffolding molecules, are under complex regulation and play a crucial role in synaptic connectivity and plasticity, as well as in higher brain functions. An increasing number of studies have established ubiquitination and proteasome-mediated degradation as universal mechanisms in the control of synaptic protein homeostasis. In this paper, we focus on the role of the ubiquitin-proteasome system (UPS) in the turnover of major neurotransmitter receptors, including glutamatergic and nonglutamatergic receptors, as well as postsynaptic receptor-interacting proteins.

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Mennerick, Steven, Weixing Shen, Wanyan Xu, Ann Benz, Kohichi Tanaka, Keiko Shimamoto, Keith E. Isenberg, James E. Krause, and Charles F. Zorumski. "Substrate Turnover by Transporters Curtails Synaptic Glutamate Transients." Journal of Neuroscience 19, no. 21 (November 1, 1999): 9242–51. http://dx.doi.org/10.1523/jneurosci.19-21-09242.1999.

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Schwartz, J. H. "Ubiquitination, Protein Turnover, and Long-Term Synaptic Plasticity." Science Signaling 2003, no. 190 (July 8, 2003): pe26. http://dx.doi.org/10.1126/stke.2003.190.pe26.

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Cline, Hollis. "Synaptic Plasticity: Importance of Proteasome-Mediated Protein Turnover." Current Biology 13, no. 13 (July 2003): R514—R516. http://dx.doi.org/10.1016/s0960-9822(03)00443-3.

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Spangler, Samantha A., Sabine K. Schmitz, Josta T. Kevenaar, Esther de Graaff, Heidi de Wit, Jeroen Demmers, Ruud F. Toonen, and Casper C. Hoogenraad. "Liprin-α2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission." Journal of Cell Biology 201, no. 6 (June 10, 2013): 915–28. http://dx.doi.org/10.1083/jcb.201301011.

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The presynaptic active zone mediates synaptic vesicle exocytosis, and modulation of its molecular composition is important for many types of synaptic plasticity. Here, we identify synaptic scaffold protein liprin-α2 as a key organizer in this process. We show that liprin-α2 levels were regulated by synaptic activity and the ubiquitin–proteasome system. Furthermore, liprin-α2 organized presynaptic ultrastructure and controlled synaptic output by regulating synaptic vesicle pool size. The presence of liprin-α2 at presynaptic sites did not depend on other active zone scaffolding proteins but was critical for recruitment of several components of the release machinery, including RIM1 and CASK. Fluorescence recovery after photobleaching showed that depletion of liprin-α2 resulted in reduced turnover of RIM1 and CASK at presynaptic terminals, suggesting that liprin-α2 promotes dynamic scaffolding for molecular complexes that facilitate synaptic vesicle release. Therefore, liprin-α2 plays an important role in maintaining active zone dynamics to modulate synaptic efficacy in response to changes in network activity.

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LoGiudice, L., P. Sterling, and G. Matthews. "Mobility and Turnover of Vesicles at the Synaptic Ribbon." Journal of Neuroscience 28, no. 12 (March 19, 2008): 3150–58. http://dx.doi.org/10.1523/jneurosci.5753-07.2008.

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Castello-Waldow, Tim P., Ghabiba Weston, Alessandro F. Ulivi, Alireza Chenani, Yonatan Loewenstein, Alon Chen, and Alessio Attardo. "Hippocampal neurons with stable excitatory connectivity become part of neuronal representations." PLOS Biology 18, no. 11 (November 3, 2020): e3000928. http://dx.doi.org/10.1371/journal.pbio.3000928.

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Experiences are represented in the brain by patterns of neuronal activity. Ensembles of neurons representing experience undergo activity-dependent plasticity and are important for learning and recall. They are thus considered cellular engrams of memory. Yet, the cellular events that bias neurons to become part of a neuronal representation are largely unknown. In rodents, turnover of structural connectivity has been proposed to underlie the turnover of neuronal representations and also to be a cellular mechanism defining the time duration for which memories are stored in the hippocampus. If these hypotheses are true, structural dynamics of connectivity should be involved in the formation of neuronal representations and concurrently important for learning and recall. To tackle these questions, we used deep-brain 2-photon (2P) time-lapse imaging in transgenic mice in which neurons expressing the Immediate Early Gene (IEG) Arc (activity-regulated cytoskeleton-associated protein) could be permanently labeled during a specific time window. This enabled us to investigate the dynamics of excitatory synaptic connectivity—using dendritic spines as proxies—of hippocampal CA1 (cornu ammonis 1) pyramidal neurons (PNs) becoming part of neuronal representations exploiting Arc as an indicator of being part of neuronal representations. We discovered that neurons that will prospectively express Arc have slower turnover of synaptic connectivity, thus suggesting that synaptic stability prior to experience can bias neurons to become part of representations or possibly engrams. We also found a negative correlation between stability of structural synaptic connectivity and the ability to recall features of a hippocampal-dependent memory, which suggests that faster structural turnover in hippocampal CA1 might be functional for memory.

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Heo, Seok, Graham H. Diering, Chan Hyun Na, Raja Sekhar Nirujogi, Julia L. Bachman, Akhilesh Pandey, and Richard L. Huganir. "Identification of long-lived synaptic proteins by proteomic analysis of synaptosome protein turnover." Proceedings of the National Academy of Sciences 115, no. 16 (April 2, 2018): E3827—E3836. http://dx.doi.org/10.1073/pnas.1720956115.

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Memory formation is believed to result from changes in synapse strength and structure. While memories may persist for the lifetime of an organism, the proteins and lipids that make up synapses undergo constant turnover with lifetimes from minutes to days. The molecular basis for memory maintenance may rely on a subset of long-lived proteins (LLPs). While it is known that LLPs exist, whether such proteins are present at synapses is unknown. We performed an unbiased screen using metabolic pulse-chase labeling in vivo in mice and in vitro in cultured neurons combined with quantitative proteomics. We identified synaptic LLPs with half-lives of several months or longer. Proteins in synaptic fractions generally exhibited longer lifetimes than proteins in cytosolic fractions. Protein turnover was sensitive to pharmacological manipulations of activity in neuronal cultures or in mice exposed to an enriched environment. We show that synapses contain LLPs that may underlie stabile long-lasting changes in synaptic structure and function.

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Petrov, A. M., M. R. Kasimov, and A. L. Zefirov. "Brain Cholesterol Metabolism and Its Defects: Linkage to Neurodegenerative Diseases and Synaptic Dysfunction." Acta Naturae 8, no. 1 (March 15, 2016): 58–73. http://dx.doi.org/10.32607/20758251-2016-8-1-58-73.

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Cholesterol is an important constituent of cell membranes and plays a crucial role in the compartmentalization of the plasma membrane and signaling. Brain cholesterol accounts for a large proportion of the bodys total cholesterol, existing in two pools: the plasma membranes of neurons and glial cells and the myelin membranes . Cholesterol has been recently shown to be important for synaptic transmission, and a link between cholesterol metabolism defects and neurodegenerative disorders is now recognized. Many neurodegenerative diseases are characterized by impaired cholesterol turnover in the brain. However, at which stage the cholesterol biosynthetic pathway is perturbed and how this contributes to pathogenesis remains unknown. Cognitive deficits and neurodegeneration may be associated with impaired synaptic transduction. Defects in cholesterol biosynthesis can trigger dysfunction of synaptic transmission. In this review, an overview of cholesterol turnover under physiological and pathological conditions is presented (Huntingtons, Niemann-Pick type C diseases, Smith-Lemli-Opitz syndrome). We will discuss possible mechanisms by which cholesterol content in the plasma membrane influences synaptic processes. Changes in cholesterol metabolism in Alzheimers disease, Parkinsons disease, and autistic disorders are beyond the scope of this review and will be summarized in our next paper.

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Ryan, Timothy A., Noam E. Ziv, and Stephen J. Smith. "Potentiation of Evoked Vesicle Turnover at Individually Resolved Synaptic Boutons." Neuron 17, no. 1 (July 1996): 125–34. http://dx.doi.org/10.1016/s0896-6273(00)80286-x.

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Schaefer, Henry, and Christopher Rongo. "KEL-8 Is a Substrate Receptor for CUL3-dependent Ubiquitin Ligase That Regulates Synaptic Glutamate Receptor Turnover." Molecular Biology of the Cell 17, no. 3 (March 2006): 1250–60. http://dx.doi.org/10.1091/mbc.e05-08-0794.

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The regulated localization of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (AMPARs) to synapses is an important component of synaptic signaling and plasticity. Regulated ubiquitination and endocytosis determine the synaptic levels of AMPARs, but it is unclear which factors conduct these processes. To identify genes that regulate AMPAR synaptic abundance, we screened for mutants that accumulate high synaptic levels of the AMPAR subunit GLR-1 in Caenorhabditis elegans. GLR-1 is localized to postsynaptic clusters, and mutants for the BTB-Kelch protein KEL-8 have increased GLR-1 levels at clusters, whereas the levels and localization of other synaptic proteins seem normal. KEL-8 is a neuronal protein and is localized to sites adjacent to GLR-1 postsynaptic clusters along the ventral cord neurites. KEL-8 is required for the ubiquitin-mediated turnover of GLR-1 subunits, and kel-8 mutants show an increased frequency of spontaneous reversals in locomotion, suggesting increased levels of GLR-1 are present at synapses. KEL-8 binds to CUL-3, a Cullin 3 ubiquitin ligase subunit that we also find mediates GLR-1 turnover. Our findings indicate that KEL-8 is a substrate receptor for Cullin 3 ubiquitin ligases that is required for the proteolysis of GLR-1 receptors and suggest a novel postmitotic role in neurons for Kelch/CUL3 ubiquitin ligases.

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Cohen, Laurie D., and Noam E. Ziv. "Recent insights on principles of synaptic protein degradation." F1000Research 6 (May 15, 2017): 675. http://dx.doi.org/10.12688/f1000research.10599.1.

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Maintaining synaptic integrity and function depends on the continuous removal and degradation of aged or damaged proteins. Synaptic protein degradation has received considerable attention in the context of synaptic plasticity and growing interest in relation to neurodegenerative and other disorders. Conversely, less attention has been given to constitutive, ongoing synaptic protein degradation and the roles canonical degradation pathways play in these processes. Here we briefly review recent progress on this topic and new experimental approaches which have expedited such progress and highlight several emerging principles. These include the realization that synaptic proteins typically have unusually long lifetimes, as might be expected from the remote locations of most synaptic sites; the possibility that degradation pathways can change with time from synthesis, cellular context, and physiological input; and that degradation pathways, other than ubiquitin-proteasomal-mediated degradation, might play key roles in constitutive protein degradation at synaptic sites. Finally, we point to the importance of careful experimental design and sufficiently sensitive techniques for studying synaptic protein degradation, which bring into account their slow turnover rates and complex life cycles.

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Acker, Daniel, Suzanne Paradis, and Paul Miller. "Stable memory and computation in randomly rewiring neural networks." Journal of Neurophysiology 122, no. 1 (July 1, 2019): 66–80. http://dx.doi.org/10.1152/jn.00534.2018.

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Our brains must maintain a representation of the world over a period of time much longer than the typical lifetime of the biological components producing that representation. For example, recent research suggests that dendritic spines in the adult mouse hippocampus are transient with an average lifetime of ~10 days. If this is true, and if turnover is equally likely for all spines, ~95% of excitatory synapses onto a particular neuron will turn over within 30 days; however, a neuron’s receptive field can be relatively stable over this period. Here, we use computational modeling to ask how memories can persist in neural circuits such as the hippocampus and visual cortex in the face of synapse turnover. We demonstrate that Hebbian plasticity during replay of presynaptic activity patterns can integrate newly formed synapses into pre-existing memories. Furthermore, we find that Hebbian plasticity during replay is sufficient to stabilize the receptive fields of hippocampal place cells in a model of the grid-cell-to-place-cell transformation in CA1 and of orientation-selective cells in a model of the center-surround-to-simple-cell transformation in V1. Together, these data suggest that a simple plasticity rule, correlative Hebbian plasticity of synaptic strengths, is sufficient to preserve neural representations in the face of synapse turnover, even in the absence of activity-dependent structural plasticity. NEW & NOTEWORTHY Recent research suggests that synapses turn over rapidly in some brain structures; however, memories seem to persist for much longer. We show that Hebbian plasticity of synaptic strengths during reactivation events can preserve memory in computational models of hippocampal and cortical networks despite turnover of all synapses. Our results suggest that memory can be stored in the correlation structure of a network undergoing rapid synaptic remodeling.

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Wenzel, Michael, Alexander Leunig, Shuting Han, Darcy S. Peterka, and Rafael Yuste. "Prolonged anesthesia alters brain synaptic architecture." Proceedings of the National Academy of Sciences 118, no. 7 (February 10, 2021): e2023676118. http://dx.doi.org/10.1073/pnas.2023676118.

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Prolonged medically induced coma (pMIC) is carried out routinely in intensive care medicine. pMIC leads to cognitive impairment, yet the underlying neuromorphological correlates are still unknown, as no direct studies of MIC exceeding ∼6 h on neural circuits exist. Here, we establish pMIC (up to 24 h) in adolescent and mature mice, and combine longitudinal two-photon imaging of cortical synapses with repeated behavioral object recognition assessments. We find that pMIC affects object recognition, and that it is associated with enhanced synaptic turnover, generated by enhanced synapse formation during pMIC, while the postanesthetic period is dominated by synaptic loss. Our results demonstrate major side effects of prolonged anesthesia on neural circuit structure.

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Theodosis, Dionysia T., Andrei Trailin, and Dominique A. Poulain. "Remodeling of astrocytes, a prerequisite for synapse turnover in the adult brain? Insights from the oxytocin system of the hypothalamus." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 290, no. 5 (May 2006): R1175—R1182. http://dx.doi.org/10.1152/ajpregu.00755.2005.

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Neurons, including their synapses, are generally ensheathed by fine processes of astrocytes, but this glial coverage can be altered under different physiological conditions that modify neuronal activity. Changes in synaptic connectivity accompany astrocytic transformations so that an increased number of synapses are associated with reduced astrocytic coverage of postsynaptic elements, whereas synaptic numbers are reduced on reestablishment of glial coverage. A system that exemplifies activity-dependent structural synaptic plasticity in the adult brain is the hypothalamo-neurohypophysial system, and in particular, its oxytocin component. Under strong, prolonged activation (parturition, lactation, chronic dehydration), extensive portions of somatic and dendritic surfaces of magnocellular oxytocin neurons are freed of intervening astrocytic processes and become directly juxtaposed. Concurrently, they are contacted by an increased number of inhibitory and excitatory synapses. Once stimulation is over, astrocytic processes again cover oxytocinergic surfaces and synaptic numbers return to baseline levels. Such observations indicate that glial ensheathment of neurons is of consequence to neuronal function, not only directly, for example by modifying synaptic transmission, but indirectly as well, by preparing neuronal surfaces for synapse turnover.

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Soykan, Tolga, Volker Haucke, and Marijn Kuijpers. "Mechanism of synaptic protein turnover and its regulation by neuronal activity." Current Opinion in Neurobiology 69 (August 2021): 76–83. http://dx.doi.org/10.1016/j.conb.2021.02.006.

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Soltesz, I., Z. Zhou, G. M. Smith, and I. Mody. "Rapid turnover rate of the hippocampal synaptic NMDA-R1 receptor subunits." Neuroscience Letters 181, no. 1-2 (November 1994): 5–8. http://dx.doi.org/10.1016/0304-3940(94)90547-9.

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Zhou, Jiechao, Hei-Man Chow, Yan Liu, Di Wu, Meng Shi, Jieyin Li, Lei Wen, et al. "Cyclin-Dependent Kinase 5–Dependent BAG3 Degradation Modulates Synaptic Protein Turnover." Biological Psychiatry 87, no. 8 (April 2020): 756–69. http://dx.doi.org/10.1016/j.biopsych.2019.11.013.

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Nair, Ramya, Juliane Lauks, SangYong Jung, Nancy E. Cooke, Heidi de Wit, Nils Brose, Manfred W. Kilimann, Matthijs Verhage, and JeongSeop Rhee. "Neurobeachin regulates neurotransmitter receptor trafficking to synapses." Journal of Cell Biology 200, no. 1 (December 31, 2012): 61–80. http://dx.doi.org/10.1083/jcb.201207113.

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The surface density of neurotransmitter receptors at synapses is a key determinant of synaptic efficacy. Synaptic receptor accumulation is regulated by the transport, postsynaptic anchoring, and turnover of receptors, involving multiple trafficking, sorting, motor, and scaffold proteins. We found that neurons lacking the BEACH (beige-Chediak/Higashi) domain protein Neurobeachin (Nbea) had strongly reduced synaptic responses caused by a reduction in surface levels of glutamate and GABAA receptors. In the absence of Nbea, immature AMPA receptors accumulated early in the biosynthetic pathway, and mature N-methyl-d-aspartate, kainate, and GABAA receptors did not reach the synapse, whereas maturation and surface expression of other membrane proteins, synapse formation, and presynaptic function were unaffected. These data show that Nbea regulates synaptic transmission under basal conditions by targeting neurotransmitter receptors to synapses.

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Borisova, Tatiana, and Arsenii Borysov. "Putative duality of presynaptic events." Reviews in the Neurosciences 27, no. 4 (June 1, 2016): 377–83. http://dx.doi.org/10.1515/revneuro-2015-0044.

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AbstractThe main structure in the brain responsible not only for nerve signal transmission but also for its simultaneous regulation is chemical synapse, where presynaptic nerve terminals are of considerable importance providing release of neurotransmitters. Analyzing transport of glutamate, the major excitatory neurotransmitter in the mammalian CNS, the authors suggest that there are two main relatively independent mechanisms at the presynaptic level that can influence the extracellular glutamate concentration, and so signaling, and its regulation. The first one is well-known precisely regulated compound exocytosis of synaptic vesicles containing neurotransmitters stimulated by membrane depolarization, which increases significantly glutamate concentration in the synaptic cleft and initiates glutamate signaling through postsynaptic glutamate receptors. The second one is permanent glutamate turnover across the plasma membrane that occurs without stimulation and is determined by simultaneous non-pathological transporter-mediated release of glutamate thermodynamically synchronized with uptake. Permanent glutamate turnover is responsible for maintenance of dynamic glutamatein/glutamateoutgradient resulting in the establishment of a flexible extracellular level of glutamate, which can be unique for each synapse because of dependence on individual presynaptic parameters. These two mechanisms, i.e. exocytosis and transporter-mediated glutamate turnover, are both precisely regulated but do not directly interfere with each other, because they have different intracellular sources of glutamate in nerve terminals for release purposes, i.e. glutamate pool of synaptic vesicles and the cytoplasm, respectively. This duality can set up a presynaptic base for memory consolidation and storage, maintenance of neural circuits, long-term potentiation, and plasticity. Arguments against this suggestion are also considered.

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Martinez-Pena y Valenzuela, Isabel, and Mohammed Akaaboune. "The Metabolic Stability of the Nicotinic Acetylcholine Receptor at the Neuromuscular Junction." Cells 10, no. 2 (February 9, 2021): 358. http://dx.doi.org/10.3390/cells10020358.

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The clustering and maintenance of nicotinic acetylcholine receptors (AChRs) at high density in the postsynaptic membrane is a hallmark of the mammalian neuromuscular junction (NMJ). The regulation of receptor density/turnover rate at synapses is one of the main thrusts of neurobiology because it plays an important role in synaptic development and synaptic plasticity. The state-of-the-art imaging revealed that AChRs are highly dynamic despite the overall structural stability of the NMJ over the lifetime of the animal. This review highlights the work on the metabolic stability of AChRs at developing and mature NMJs and discusses the role of synaptic activity and the regulatory signaling pathways involved in the dynamics of AChRs.

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McDade, Donna M., Ann-Marie Conway, Allan B. James, and Brian J. Morris. "Activity-dependent gene transcription as a long-term influence on receptor signalling." Biochemical Society Transactions 37, no. 6 (November 19, 2009): 1375–77. http://dx.doi.org/10.1042/bst0371375.

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The regulation of synaptic glutamate receptor and GABAAR (γ-aminobutyric acid subtype A receptor) levels is a key component of synaptic plasticity. Most forms of neuronal plasticity are associated with the induction of the transcription factor zif268 (egr1). Hence, it is predicted that zif268 may regulate transcription of genes associated with glutamate receptors and/or GABAARs. It turns out that receptor regulation by zif268 tends to be indirect. Induction of zif268 in neurons leads to altered expression of proteasome subunit and proteasome-regulatory genes, thereby changing the capacity of the neuron to degrade synaptic proteins, including receptors and receptor subunits. In addition, zif268 alters the transcription of genes associated with GABAAR expression and trafficking, such as ubiquilin and gephyrin. This indirect regulation of receptor turnover is likely to contribute to the delayed, but long-lasting, phases of synaptic plasticity and also to the synaptic dysfunction associated with diseases such as schizophrenia and Alzheimer's disease, where zif268 expression is reduced.

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Schreiber, Joerg, Marlene J. Végh, Julia Dawitz, Tim Kroon, Maarten Loos, Dorthe Labonté, Ka Wan Li, et al. "Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels." Journal of Cell Biology 211, no. 3 (November 2, 2015): 569–86. http://dx.doi.org/10.1083/jcb.201506048.

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Synaptic plasticity requires remodeling of the actin cytoskeleton. Although two actin isoforms, β- and γ-actin, are expressed in dendritic spines, the specific contribution of γ-actin in the expression of synaptic plasticity is unknown. We show that synaptic γ-actin levels are regulated by the E3 ubiquitin ligase TRIM3. TRIM3 protein and Actg1 transcript are colocalized in messenger ribonucleoprotein granules responsible for the dendritic targeting of messenger RNAs. TRIM3 polyubiquitylates γ-actin, most likely cotranslationally at synaptic sites. Trim3−/− mice consequently have increased levels of γ-actin at hippocampal synapses, resulting in higher spine densities, increased long-term potentiation, and enhanced short-term contextual fear memory consolidation. Interestingly, hippocampal deletion of Actg1 caused an increase in long-term fear memory. Collectively, our findings suggest that temporal control of γ-actin levels by TRIM3 is required to regulate the timing of hippocampal plasticity. We propose a model in which TRIM3 regulates synaptic γ-actin turnover and actin filament stability and thus forms a transient inhibitory constraint on the expression of hippocampal synaptic plasticity.

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Fernandes, Ana Clara, Valerie Uytterhoeven, Sabine Kuenen, Yu-Chun Wang, Jan R. Slabbaert, Jef Swerts, Jaroslaw Kasprowicz, Stein Aerts, and Patrik Verstreken. "Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration." Journal of Cell Biology 207, no. 4 (November 24, 2014): 453–62. http://dx.doi.org/10.1083/jcb.201406026.

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Synaptic demise and accumulation of dysfunctional proteins are thought of as common features in neurodegeneration. However, the mechanisms by which synaptic proteins turn over remain elusive. In this paper, we study Drosophila melanogaster lacking active TBC1D24/Skywalker (Sky), a protein that in humans causes severe neurodegeneration, epilepsy, and DOOR (deafness, onychdystrophy, osteodystrophy, and mental retardation) syndrome, and identify endosome-to-lysosome trafficking as a mechanism for degradation of synaptic vesicle-associated proteins. In fly sky mutants, synaptic vesicles traveled excessively to endosomes. Using chimeric fluorescent timers, we show that synaptic vesicle-associated proteins were younger on average, suggesting that older proteins are more efficiently degraded. Using a genetic screen, we find that reducing endosomal-to-lysosomal trafficking, controlled by the homotypic fusion and vacuole protein sorting (HOPS) complex, rescued the neurotransmission and neurodegeneration defects in sky mutants. Consistently, synaptic vesicle proteins were older in HOPS complex mutants, and these mutants also showed reduced neurotransmission. Our findings define a mechanism in which synaptic transmission is facilitated by efficient protein turnover at lysosomes and identify a potential strategy to suppress defects arising from TBC1D24 mutations in humans.

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Sheehan, Patricia, and Clarissa L. Waites. "Coordination of synaptic vesicle trafficking and turnover by the Rab35 signaling network." Small GTPases 10, no. 1 (January 27, 2017): 54–63. http://dx.doi.org/10.1080/21541248.2016.1270392.

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Uytterhoeven, Valerie, Elsa Lauwers, Ine Maes, Katarzyna Miskiewicz, Manuel N. Melo, Jef Swerts, Sabine Kuenen, et al. "Hsc70-4 Deforms Membranes to Promote Synaptic Protein Turnover by Endosomal Microautophagy." Neuron 88, no. 4 (November 2015): 735–48. http://dx.doi.org/10.1016/j.neuron.2015.10.012.

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Speese, Sean D., Nick Trotta, Chris K. Rodesch, Bharathi Aravamudan, and Kendal Broadie. "The Ubiquitin Proteasome System Acutely Regulates Presynaptic Protein Turnover and Synaptic Efficacy." Current Biology 13, no. 11 (May 2003): 899–910. http://dx.doi.org/10.1016/s0960-9822(03)00338-5.

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Kim, Ji-Il, Hyoung-Gon Ko, Jun-Hyeok Choi, Dong Ik Park, Sukjae Kang, Chae-Seok Lim, Su-Eon Sim, et al. "Peripheral nerve injury induces rapid turnover of cortical NCAM1 and synaptic reorganization." IBRO Reports 6 (September 2019): S403. http://dx.doi.org/10.1016/j.ibror.2019.07.1285.

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Ando, Susumu, Yasukazu Tanaka, Yuriko Toyoda (nee Ono), Kazuo Kon, and Sei-ichi Kawashima. "Turnover of synaptic membranes: Age-related changes and modulation by dietary restriction." Journal of Neuroscience Research 70, no. 3 (October 18, 2002): 290–97. http://dx.doi.org/10.1002/jnr.10352.

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Ko, Hyoung-Gon, Jun-Hyeok Choi, Dong Ik Park, SukJae Joshua Kang, Chae-Seok Lim, Su-Eon Sim, Jaehoon Shim, et al. "Rapid Turnover of Cortical NCAM1 Regulates Synaptic Reorganization after Peripheral Nerve Injury." Cell Reports 22, no. 3 (January 2018): 748–59. http://dx.doi.org/10.1016/j.celrep.2017.12.059.

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Chambers, R. Andrew, and Susan K. Conroy. "Network Modeling of Adult Neurogenesis: Shifting Rates of Neuronal Turnover Optimally Gears Network Learning according to Novelty Gradient." Journal of Cognitive Neuroscience 19, no. 1 (January 2007): 1–12. http://dx.doi.org/10.1162/jocn.2007.19.1.1.

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Apoptotic and neurogenic events in the adult hippocampus are hypothesized to play a role in cognitive responses to new contexts. Corticosteroid-mediated stress responses and other neural processes invoked by substantially novel contextual changes may regulate these processes. Using elementary three-layer neural networks that learn by incremental synaptic plasticity, we explored whether the cognitive effects of differential regimens of neuronal turnover depend on the environmental context in terms of the degree of novelty in the new information to be learned. In “adult” networks that had achieved mature synaptic connectivity upon prior learning of the Roman alphabet, imposition of apoptosis/neurogenesis before learning increasingly novel information (alternate Roman < Russian < Hebrew) reveals optimality of informatic cost benefits when rates of turnover are geared in proportion to the degree of novelty. These findings predict that flexible control of rates of apoptosis-neurogenesis within plastic, mature neural systems optimizes learning attributes under varying degrees of contextual change, and that failures in this regulation may define a role for adult hippocampal neurogenesis in novelty- and stress-responsive psychiatric disorders.

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Uzbekov, M. "FC13-09 - Antidepressant tianeptine (TIA) action is based on the acceleration of serotonin turnover in the synapse: a hypothesis." European Psychiatry 26, S2 (March 2011): 1890. http://dx.doi.org/10.1016/s0924-9338(11)73594-5.

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IntroductionNeurochemical mechanism of TIA action is not clear.AimTo develop possible mechanism of TIA action in patients with anxious depression (Uzbekov et al., 2006, 2009).ResultsIt was found twofold increase of platelet monoamine oxidase (MAO) activity in depressed patients and its significant decrease under TIA action.DiscussionSynapse is considered as a complex biological system (nerve ending + astrocytes). It is supposed that at normal conditions about 75% of serotonin released in synaptic cleft undergoes functional inactivation by its reuptake in presynaptic ending. The remaining serotonin is taken up by astroglia and is undergone its irreversible (chemical) inactivation under MAO action.According to our hypothesis TIA enhancing serotonin reuptake decreases serotonin level in synaptic cleft. Simultaneously in patients-responders we have established the decrease (inhibition) of MAO activity that promotes increase of serotonin concentration in synaptic cleft. It has been shown that TIA activates serotonin release from presynaptic ending (Labrid et al., 1992). Thus TIA enhances not only serotonin reuptake but simultaneously activates its surge from the ending into synaptic cleft. We conclude that under TIA action serotonin turnover rate in the synapse is increased that promotes increase in the unit of time serotonin concentration on postsynaptic receptors; this process is accompanied by decrease of MAO activity.ConclusionThe first time in the literature we propose the hypothesis about neurochemical mechanism of TIA action. Proposed mechanism mainly refers to the first acute phase of TIA action directed on the normalization of serotonergic neurotransmission.

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Sedlak, Thomas W., Bindu D. Paul, Gregory M. Parker, Lynda D. Hester, Adele M. Snowman, Yu Taniguchi, Atsushi Kamiya, Solomon H. Snyder, and Akira Sawa. "The glutathione cycle shapes synaptic glutamate activity." Proceedings of the National Academy of Sciences 116, no. 7 (January 28, 2019): 2701–6. http://dx.doi.org/10.1073/pnas.1817885116.

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Glutamate is the most abundant excitatory neurotransmitter, present at the bulk of cortical synapses, and participating in many physiologic and pathologic processes ranging from learning and memory to stroke. The tripeptide, glutathione, is one-third glutamate and present at up to low millimolar intracellular concentrations in brain, mediating antioxidant defenses and drug detoxification. Because of the substantial amounts of brain glutathione and its rapid turnover under homeostatic control, we hypothesized that glutathione is a relevant reservoir of glutamate and could influence synaptic excitability. We find that drugs that inhibit generation of glutamate by the glutathione cycle elicit decreases in cytosolic glutamate and decreased miniature excitatory postsynaptic potential (mEPSC) frequency. In contrast, pharmacologically decreasing the biosynthesis of glutathione leads to increases in cytosolic glutamate and enhanced mEPSC frequency. The glutathione cycle can compensate for decreased excitatory neurotransmission when the glutamate-glutamine shuttle is inhibited. Glutathione may be a physiologic reservoir of glutamate neurotransmitter.

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Birdsall, Veronica, Konner Kirwan, Mei Zhu, Yuuta Imoto, Scott M. Wilson, Shigeki Watanabe, and Clarissa L. Waites. "Axonal transport of Hrs is activity dependent and facilitates synaptic vesicle protein degradation." Life Science Alliance 5, no. 10 (May 30, 2022): e202000745. http://dx.doi.org/10.26508/lsa.202000745.

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Turnover of synaptic vesicle (SV) proteins is vital for the maintenance of healthy and functional synapses. SV protein turnover is driven by neuronal activity in an endosomal sorting complex required for transport (ESCRT)-dependent manner. Here, we characterize a critical step in this process: axonal transport of ESCRT-0 component Hrs, necessary for sorting proteins into the ESCRT pathway and recruiting downstream ESCRT machinery to catalyze multivesicular body (MVB) formation. We find that neuronal activity stimulates the formation of presynaptic endosomes and MVBs, as well as the motility of Hrs+ vesicles in axons and their delivery to SV pools. Hrs+ vesicles co-transport ESCRT-0 component STAM1 and comprise a subset of Rab5+ vesicles, likely representing pro-degradative early endosomes. Furthermore, we identify kinesin motor protein KIF13A as essential for the activity-dependent transport of Hrs to SV pools and the degradation of SV membrane proteins. Together, these data demonstrate a novel activity- and KIF13A-dependent mechanism for mobilizing axonal transport of ESCRT machinery to facilitate the degradation of SV membrane proteins.

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Trouillas, P. "The Cerebellar Serotoninergic System and its Possible Involvement in Cerebellar Ataxia." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 20, S3 (May 1993): S78—S82. http://dx.doi.org/10.1017/s0317167100048575.

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ABSTRACT:A review concerning the characteristics of the cerebellar serotoninergic system is presented. In rat, cat and oppossum, the perikarya of origin are located in the brain stem raphe nuclei and in other brainstem structures. The projections to the cerebellar layers and deep nuclei include synaptic connections, but also non synaptic terminals, espedaily in a diffuse cortical plexus. Serotoninergic receptors have been described: 5-HT1B in the molecular layer and 5-HT2 in the inferior olive. Serotonin exerts neurophysiological effects on several target cells, directly or indirectly, presynaptically or postsynaptically. A modulatory effect on Purkinje cells is well documented. In thiamine deprived animals, a specific serotoninergic cerebellar syndrome includes a selective degeneration of the serotoninergic cerebellar system, an increase of the 5-HIAA cerebellar values and an exaggerated serotoninergic turnover. In human here-doataxias (Friedreich’s ataxia and cerebellar cortical atrophy), serotoninergic disturbances have been observed in the CSF, including low 5-HIAA values and an increased serotoninergic turnover. Therapeutic results have been obtained with L-5-HTP, a precursor of serotonin, in several conditions presenting cerebellar ataxia. L-5-HTP resistance of olivo-pontocerebellar atrophies may be explained by the destruction of serotonin-sensitive target cells, especially Purkinje cells.

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Limanaqi, Fiona, Francesca Biagioni, Carla Letizia Busceti, Larisa Ryskalin, Paola Soldani, Alessandro Frati, and Francesco Fornai. "Cell Clearing Systems Bridging Neuro-Immunity and Synaptic Plasticity." International Journal of Molecular Sciences 20, no. 9 (May 4, 2019): 2197. http://dx.doi.org/10.3390/ijms20092197.

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In recent years, functional interconnections emerged between synaptic transmission, inflammatory/immune mediators, and central nervous system (CNS) (patho)-physiology. Such interconnections rose up to a level that involves synaptic plasticity, both concerning its molecular mechanisms and the clinical outcomes related to its behavioral abnormalities. Within this context, synaptic plasticity, apart from being modulated by classic CNS molecules, is strongly affected by the immune system, and vice versa. This is not surprising, given the common molecular pathways that operate at the cross-road between the CNS and immune system. When searching for a common pathway bridging neuro-immune and synaptic dysregulations, the two major cell-clearing cell clearing systems, namely the ubiquitin proteasome system (UPS) and autophagy, take center stage. In fact, just like is happening for the turnover of key proteins involved in neurotransmitter release, antigen processing within both peripheral and CNS-resident antigen presenting cells is carried out by UPS and autophagy. Recent evidence unravelling the functional cross-talk between the cell-clearing pathways challenged the traditional concept of autophagy and UPS as independent systems. In fact, autophagy and UPS are simultaneously affected in a variety of CNS disorders where synaptic and inflammatory/immune alterations concur. In this review, we discuss the role of autophagy and UPS in bridging synaptic plasticity with neuro-immunity, while posing a special emphasis on their interactions, which may be key to defining the role of immunity in synaptic plasticity in health and disease.

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Pierrot, Nathalie, Donatienne Tyteca, Ludovic d'Auria, Ilse Dewachter, Philippe Gailly, Laurence Ris, Laetitia El Haylani, et al. "P4-036: Amyloid precursor protein regulates neuronal cholesterol turnover needed for synaptic activity." Alzheimer's & Dementia 8, no. 4S_Part_18 (July 2012): P648—P649. http://dx.doi.org/10.1016/j.jalz.2012.05.1737.

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Rabenstein, Michael, Nico Murr, Andreas Hermann, Arndt Rolfs, and Moritz J. Frech. "Alteration of GABAergic Input Precedes Neurodegeneration of Cerebellar Purkinje Cells of NPC1-Deficient Mice." International Journal of Molecular Sciences 20, no. 24 (December 13, 2019): 6288. http://dx.doi.org/10.3390/ijms20246288.

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Niemann-Pick Disease Type C1 (NPC1) is a rare hereditary neurodegenerative disease belonging to the family of lysosomal storage disorders. NPC1-patients suffer from, amongst other symptoms, ataxia, based on the dysfunction and loss of cerebellar Purkinje cells. Alterations in synaptic transmission are believed to contribute to a pathological mechanism leading to the progressive loss of Purkinje cells observed in NPC1-deficient mice. With regard to inhibitory synaptic transmission, alterations of GABAergic synapses are described but functional data are missing. For this reason, we have examined here the inhibitory GABAergic synaptic transmission of Purkinje cells of NPC1-deficient mice (NPC1−/−). Patch clamp recordings of inhibitory post-synaptic currents (IPSCs) of Purkinje cells revealed an increased frequency of GABAergic IPSCs in NPC1−/− mice. In addition, Purkinje cells of NPC1−/− mice were less amenable for modulation of synaptic transmission via the activation of excitatory NMDA-receptors (NMDA-Rs). Western blot testing disclosed a reduced protein level of phosphorylated alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) subunit GluA2 in the cerebella of NPC1−/− mice, indicating a disturbance in the internalization of GluA2-containing AMPA-Rs. Since this is triggered by the activation of NMDA-Rs, we conclude that a disturbance in the synaptic turnover of AMPA-Rs underlies the defective inhibitory GABAergic synaptic transmission. While these alterations precede obvious signs of neurodegeneration of Purkinje cells, we propose a contribution of synaptic malfunction to the initiation of the loss of Purkinje cells in NPC1. Thus, a prevention of the disturbance of synaptic transmission in early stages of the disease might display a target with which to avert progressive neurodegeneration in NPC1.

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Röder, Ira V., Kyeong-Rock Choi, Markus Reischl, Yvonne Petersen, Markus E. Diefenbacher, Manuela Zaccolo, Tullio Pozzan, and Rüdiger Rudolf. "Myosin Va cooperates with PKA RIα to mediate maintenance of the endplate in vivo." Proceedings of the National Academy of Sciences 107, no. 5 (January 19, 2010): 2031–36. http://dx.doi.org/10.1073/pnas.0914087107.

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Myosin V motor proteins facilitate recycling of synaptic receptors, including AMPA and acetylcholine receptors, in central and peripheral synapses, respectively. To shed light on the regulation of receptor recycling, we employed in vivo imaging of mouse neuromuscular synapses. We found that myosin Va cooperates with PKA on the postsynapse to maintain size and integrity of the synapse; this cooperation also regulated the lifetime of acetylcholine receptors. Myosin Va and PKA colocalized in subsynaptic enrichments. These accumulations were crucial for synaptic integrity and proper cAMP signaling, and were dependent on AKAP function, myosin Va, and an intact actin cytoskeleton. The neuropeptide and cAMP agonist, calcitonin-gene related peptide, rescued fragmentation of synapses upon denervation. We hypothesize that neuronal ligands trigger local activation of PKA, which in turn controls synaptic integrity and turnover of receptors. To this end, myosin Va mediates correct positioning of PKA in a postsynaptic microdomain, presumably by tethering PKA to the actin cytoskeleton.

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Goo, Marisa S., Laura Sancho, Natalia Slepak, Daniela Boassa, Thomas J. Deerinck, Mark H. Ellisman, Brenda L. Bloodgood, and Gentry N. Patrick. "Activity-dependent trafficking of lysosomes in dendrites and dendritic spines." Journal of Cell Biology 216, no. 8 (June 19, 2017): 2499–513. http://dx.doi.org/10.1083/jcb.201704068.

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In neurons, lysosomes, which degrade membrane and cytoplasmic components, are thought to primarily reside in somatic and axonal compartments, but there is little understanding of their distribution and function in dendrites. Here, we used conventional and two-photon imaging and electron microscopy to show that lysosomes traffic bidirectionally in dendrites and are present in dendritic spines. We find that lysosome inhibition alters their mobility and also decreases dendritic spine number. Furthermore, perturbing microtubule and actin cytoskeletal dynamics has an inverse relationship on the distribution and motility of lysosomes in dendrites. We also find trafficking of lysosomes is correlated with synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptors. Strikingly, lysosomes traffic to dendritic spines in an activity-dependent manner and can be recruited to individual spines in response to local activation. These data indicate the position of lysosomes is regulated by synaptic activity and thus plays an instructive role in the turnover of synaptic membrane proteins.

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Yang, Alex J. T., Ahmad Mohammad, Evangelia Tsiani, Aleksandar Necakov, and Rebecca E. K. MacPherson. "Chronic AMPK Activation Reduces the Expression and Alters Distribution of Synaptic Proteins in Neuronal SH-SY5Y Cells." Cells 11, no. 15 (July 31, 2022): 2354. http://dx.doi.org/10.3390/cells11152354.

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Neuronal growth and synaptic function are dependent on precise protein production and turnover at the synapse. AMPK-activated protein kinase (AMPK) represents a metabolic node involved in energy sensing and in regulating synaptic protein homeostasis. However, there is ambiguity surrounding the role of AMPK in regulating neuronal growth and health. This study examined the effect of chronic AMPK activation on markers of synaptic function and growth. Retinoic-acid-differentiated SH-SY5Y human neuroblastoma cells were treated with A-769662 (100 nM) or Compound C (30 nM) for 1, 3, or 5 days before AMPK, mTORC1, and markers for synapse function were examined. Cell morphology, neuronal marker content, and location were quantified after 5 days of treatment. AMPK phosphorylation was maintained throughout all 5 days of treatment with A-769662 and resulted in chronic mTORC1 inhibition. Lower total, soma, and neuritic neuronal marker contents were observed following 5 d of AMPK activation. Neurite protein abundance and distribution was lower following 5 days of A-769662 treatment. Our data suggest that chronic AMPK activation impacts synaptic protein content and reduces neurite protein abundance and distribution. These results highlight a distinct role that metabolism plays on markers of synapse health and function.

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Journal articles on the topic 'Synaptic turnover'

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