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Burak Tan Department of Physiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey

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Esra Tufan Department of Physiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey

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Özlem Barutçu Department of Physiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey

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Ezgi Aslan-Gülpınar Department of Physiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey

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Nurcan Dursun Department of Physiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey

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Cem Süer Department of Physiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey

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https://orcid.org/0000-0002-6455-6644
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Abstract

The aim of this study is to show the relationship between the change in the strengthening of synaptic plasticity and tau phosphorylation and tau-kinases and phosphatase. The averages of the field excitatory-postsynaptic potential (fEPSP) and population spike (PS) in the last 5 min were used as a measure of LTP, LTD and MP. Total and phosphorylated levels of tau, kinases and phosphatases were evaluated by western blot and mRNA levels were evaluated by RT-qPCR. The stimulation of synapses by HFS and LFS+HFS increased the phosphorylation of total-tau and phospho-tau at the Thr181, Ser202/Thr205, Ser396 and Ser416 residues, and these were accompanied by increased enzymatic activity of Akt, ERK1/2. The increased phosphorylation of tau may mediate maintenance of LTP. If the increase in phosphorylation of tau cannot be prevented, together with inhibition of the subsequent LTP, this may indicate that the physiological role of hyperphosphorylated tau in synaptic plasticity may extend to pathological processes.

  • 1.

    Panda D, Goode BL, Feinstein SC, Wilson L. Kinetic stabilization of microtubule dynamics at steady state by tau and microtubule-binding domains of tau. Biochemistry 1995; 34(35): 1111727. https://doi.org/10.1021/bi00035a017.

    • Search Google Scholar
    • Export Citation
  • 2.

    Ittner A, Ittner LM. Dendritic tau in Alzheimer's disease. Neuron 2018; 99(1): 1327. https://doi.org/10.1016/j.neuron.2018.06.003.

  • 3.

    Regan P, Piers T, Yi JH, Kim DH, Huh S, Park SJ, et al. Tau phosphorylation at serine 396 residue is required for hippocampal LTD. J Neurosci 2015; 35(12): 480412. https://doi.org/10.1523/JNEUROSCI.2842-14.2015.

    • Search Google Scholar
    • Export Citation
  • 4.

    Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S, et al. Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Philos Trans R Soc Lond B Biol Sci 2014; 369(1633): 20130144. https://doi.org/10.1098/rstb.2013.0144.

    • Search Google Scholar
    • Export Citation
  • 5.

    Babür E, Tan B, Delibaş S, Yousef M, Dursun N, Süer C. Depotentiation of long-term potentiation is associated with epitope-specific Tau hyper-/hypophosphorylation in the hippocampus of adult rats. J Mol Neurosci 2019; 67(2): 193203. https://doi.org/10.1007/s12031-018-1224-x.

    • Search Google Scholar
    • Export Citation
  • 6.

    Billingsley ML, Kincaid RL. Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochem J 1997; 323(Pt 3): 57791. https://doi.org/10.1042/bj3230577.

    • Search Google Scholar
    • Export Citation
  • 7.

    Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 2005; 1739(2–3): 198210. https://doi.org/10.1016/j.bbadis.2004.09.008.

    • Search Google Scholar
    • Export Citation
  • 8.

    Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 1986; 83(13): 49137. https://doi.org/10.1073/pnas.83.13.4913.

    • Search Google Scholar
    • Export Citation
  • 9.

    Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A 1994; 91(12): 55626. https://doi.org/10.1073/pnas.91.12.5562.

    • Search Google Scholar
    • Export Citation
  • 10.

    Sarubbo F, Ramis MR, Tejada S, Jimenez-Garcia M, Esteban S, Miralles A, et al Resveratrol improves episodic-like memory and motor coordination through modulating neuroinflammation in old rats. J Funct Foods 2023; 104: 105533. https://doi.org/10.1016/j.jff.2023.105533.

    • Search Google Scholar
    • Export Citation
  • 11.

    Santos AR, Mele M, Vaz SH, Kellermayer B, Grimaldi M, Colino-Oliveira M, et al. Differential role of the proteasome in the early and late phases of BDNF-induced facilitation of LTP. J Neurosci 2015; 35(8): 331929. https://doi.org/10.1523/JNEUROSCI.4521-14.2015.

    • Search Google Scholar
    • Export Citation
  • 12.

    Artis AS, Bitiktas S, Taskin E, Dolu N, Liman N, Suer C. Experimental hypothyroidism delays field excitatory post-synaptic potentials and disrupts hippocampal long-term potentiation in the dentate gyrus of hippocampal formation and Y-maze performance in adult rats. J Neuroendocrinol 2012; 24(3): 42233. https://doi.org/10.1111/j.1365-2826.2011.02253.x.

    • Search Google Scholar
    • Export Citation
  • 13.

    Impey S, Obrietan K, Storm DR. Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 1999; 23(1): 114. https://doi.org/10.1016/s0896-6273(00)80747-3.

    • Search Google Scholar
    • Export Citation
  • 14.

    Bruchas MR, Schindler AG, Shankar H, Messinger DI, Miyatake M, Land BB, et al. Selective p38alpha MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction. Neuron 2011; 71(3): 498511. https://doi.org/10.1016/j.neuron.2011.06.011.

    • Search Google Scholar
    • Export Citation
  • 15.

    Bolshakov VY, Carboni L, Cobb MH, Siegelbaum SA, Belardetti F. Dual MAP kinase pathways mediate opposing forms of long-term plasticity at CA3-CA1 synapses. Nat Neurosci 2000; 3(11): 110712. https://doi.org/10.1038/80624.

    • Search Google Scholar
    • Export Citation
  • 16.

    Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell 2000; 103(2): 23952. https://doi.org/10.1016/s0092-8674(00)00116-1.

    • Search Google Scholar
    • Export Citation
  • 17.

    Lai KO, Ip NY. Recent advances in understanding the roles of Cdk5 in synaptic plasticity. Biochim Biophys Acta 2009; 1792(8): 7415. https://doi.org/10.1016/j.bbadis.2009.05.001.

    • Search Google Scholar
    • Export Citation
  • 18.

    Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 1989; 3(4): 51926. https://doi.org/10.1016/0896-6273(89)90210-9.

    • Search Google Scholar
    • Export Citation
  • 19.

    Andreadis A, Brown WM, Kosik KS. Structure and novel exons of the human tau gene. Biochemistry 1992; 31(43): 1062633. https://doi.org/10.1021/bi00158a027.

    • Search Google Scholar
    • Export Citation
  • 20.

    Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A 1988; 85(11): 40515. https://doi.org/10.1073/pnas.85.11.4051.

    • Search Google Scholar
    • Export Citation
  • 21.

    Taube JS, Schwartzkroin PA. Mechanisms of long-term potentiation: EPSP/spike dissociation, intradendritic recordings, and glutamate sensitivity. J Neurosci 1988; 8(5): 163244. https://doi.org/10.1523/JNEUROSCI.08-05-01632.1988.

    • Search Google Scholar
    • Export Citation
  • 22.

    Chavez-Noriega L, Bliss T, Halliwell J. The EPSP-spike (ES) component of long-term potentiation in the rat hippocampal slice is modulated by GABAergic but not cholinergic mechanisms. Neurosci Lett 1989; 104(1–2): 5864. https://doi.org/10.1016/0304-3940(89)90329-7.

    • Search Google Scholar
    • Export Citation
  • 23.

    Zucker RS. Calcium- and activity-dependent synaptic plasticity. Curr Opin Neurobiol 1999; 9(3): 30513. https://doi.org/10.1016/s0959-4388(99)80045-2.

    • Search Google Scholar
    • Export Citation
  • 24.

    Evans RC, Blackwell KT. Calcium: amplitude, duration, or location? Biol Bull 2015; 228(1): 7583. https://doi.org/10.1086/BBLv228n1p75.

    • Search Google Scholar
    • Export Citation
  • 25.

    Norris CM, Korol DL, Foster TC. Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging. J Neurosci 1996; 16(17): 538292. https://doi.org/10.1523/JNEUROSCI.16-17-05382.1996.

    • Search Google Scholar
    • Export Citation
  • 26.

    Tan B, Aslan-Gulpinar E, Dursun N, Suer C. N-methyl-D-aspartate receptor blockade reduces plasticity-related tau expression and phosphorylation of tau at Ser416 residue but not Thr231 residue. Exp Brain Res 2021; 239(5): 162737. https://doi.org/10.1007/s00221-021-06090-z.

    • Search Google Scholar
    • Export Citation
  • 27.

    Clopath C, Ziegler L, Vasilaki E, Busing L, Gerstner W. Tag-trigger-consolidation: a model of early and late long-term-potentiation and depression. PLoS Comput Biol 2008; 4(12): e1000248. https://doi.org/10.1371/journal.pcbi.1000248.

    • Search Google Scholar
    • Export Citation
  • 28.

    Young JZ, Nguyen PV. Homosynaptic and heterosynaptic inhibition of synaptic tagging and capture of long-term potentiation by previous synaptic activity. J Neurosci 2005; 25(31): 722131. https://doi.org/10.1523/JNEUROSCI.0909-05.2005.

    • Search Google Scholar
    • Export Citation
  • 29.

    Frey U, Morris RG. Synaptic tagging and long-term potentiation. Nature 1997; 385(6616): 5336. https://doi.org/10.1038/385533a0.

  • 30.

    Tan B, Dursun N, Suer C. Comparison of the subsequent LTP in hippocampal synapses primed by low frequency stimulations ranging from 0.5 to 5 Hz: an in vivo study. Neurosci Lett 2022; 767: 136311. https://doi.org/10.1016/j.neulet.2021.136311.

    • Search Google Scholar
    • Export Citation
  • 31.

    Christie BR, Stellwagen D, Abraham WC. Reduction of the threshold for long-term potentiation by prior theta-frequency synaptic activity. Hippocampus 1995; 5(1): 529. https://doi.org/10.1002/hipo.450050107.

    • Search Google Scholar
    • Export Citation
  • 32.

    Fonseca R, Vabulas RM, Hartl FU, Bonhoeffer T, Nagerl UV. A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP. Neuron 2006; 52(2): 23945. https://doi.org/10.1016/j.neuron.2006.08.015.

    • Search Google Scholar
    • Export Citation
  • 33.

    Jarome TJ, Helmstetter FJ. Protein degradation and protein synthesis in long-term memory formation. Front Mol Neurosci 2014; 7: 61. https://doi.org/10.3389/fnmol.2014.00061.

    • Search Google Scholar
    • Export Citation
  • 34.

    Fioravante D, Byrne JH. Protein degradation and memory formation. Brain Res Bull 2011; 85(1–2): 1420. https://doi.org/10.1016/j.brainresbull.2010.11.002.

    • Search Google Scholar
    • Export Citation
  • 35.

    Munton RP, Tweedie-Cullen R, Livingstone-Zatchej M, Weinandy F, Waidelich M, Longo D, et al. Qualitative and quantitative analyses of protein phosphorylation in naive and stimulated mouse synaptosomal preparations. Mol Cell Proteomics 2007; 6(2): 28393. https://doi.org/10.1074/mcp.M600046-MCP200.

    • Search Google Scholar
    • Export Citation
  • 36.

    Trinidad JC, Thalhammer A, Specht CG, Lynn AJ, Baker PR, Schoepfer R, et al. Quantitative analysis of synaptic phosphorylation and protein expression. Mol Cell Proteomics 2008; 7(4): 68496. https://doi.org/10.1074/mcp.M700170-MCP200.

    • Search Google Scholar
    • Export Citation
  • 37.

    Westenbroek RE, Merrick DK, Catterall WA. Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons. Neuron 1989; 3(6): 695704. https://doi.org/10.1016/0896-6273(89)90238-9.

    • Search Google Scholar
    • Export Citation
  • 38.

    James TF, Nenov MN, Wildburger NC, Lichti CF, Luisi J, Vergara F, et al. The Nav1.2 channel is regulated by GSK3. Biochim Biophys Acta 2015; 1850(4): 83244. https://doi.org/10.1016/j.bbagen.2015.01.011.

    • Search Google Scholar
    • Export Citation
  • 39.

    Persson AK, Gasser A, Black JA, Waxman SG. Nav1.7 accumulates and co-localizes with phosphorylated ERK1/2 within transected axons in early experimental neuromas. Exp Neurol 2011; 230(2): 2739. https://doi.org/10.1016/j.expneurol.2011.05.005.

    • Search Google Scholar
    • Export Citation
  • 40.

    Hughes K, Nikolakaki E, Plyte SE, Totty NF, Woodgett JR. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J 1993; 12(2): 8038. https://doi.org/10.1002/j.1460-2075.1993.tb05715.x.

    • Search Google Scholar
    • Export Citation
  • 41.

    Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, et al. LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron 2007; 53(5): 70317. https://doi.org/10.1016/j.neuron.2007.01.029.

    • Search Google Scholar
    • Export Citation
  • 42.

    Martin L, Latypova X, Wilson CM, Magnaudeix A, Perrin ML, Terro F. Tau protein phosphatases in Alzheimer's disease: the leading role of PP2A. Ageing Res Rev 2013; 12(1): 3949. https://doi.org/10.1016/j.arr.2012.06.008.

    • Search Google Scholar
    • Export Citation
  • 43.

    Mansuy IM, Shenolikar S. Protein serine/threonine phosphatases in neuronal plasticity and disorders of learning and memory. Trends Neurosci 2006; 29(12): 67986. https://doi.org/10.1016/j.tins.2006.10.004.

    • Search Google Scholar
    • Export Citation
  • 44.

    Foley K, McKee C, Nairn AC, Xia H. Regulation of synaptic Transmission and plasticity by protein phosphatase 1. J Neurosci 2021; 41(14): 304050. https://doi.org/10.1523/JNEUROSCI.2026-20.2021.

    • Search Google Scholar
    • Export Citation
  • 45.

    Mulkey RM, Herron CE, Malenka RC. An essential role for protein phosphatases in hippocampal long-term depression. Science 1993; 261(5124): 10515. https://doi.org/10.1126/science.8394601.

    • Search Google Scholar
    • Export Citation
  • 46.

    Mauna JC, Miyamae T, Pulli B, Thiels E. Protein phosphatases 1 and 2A are both required for long-term depression and associated dephosphorylation of cAMP response element binding protein in hippocampal area CA1. Hippocampus 2011; 21(10): 1093104. https://doi.org/10.1002/hipo.20823.

    • Search Google Scholar
    • Export Citation
  • 47.

    Mondragon-Rodriguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M, Leclerc N, et al. Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem 2012; 287(38): 3204053. https://doi.org/10.1074/jbc.M112.401240.

    • Search Google Scholar
    • Export Citation
  • 48.

    Medeiros R, Baglietto-Vargas D, LaFerla FM. The role of tau in Alzheimer's disease and related disorders. CNS Neurosci Ther 2011; 17(5): 51424. https://doi.org/10.1111/j.1755-5949.2010.00177.x.

    • Search Google Scholar
    • Export Citation
  • 49.

    Biundo F, Del Prete D, Zhang H, Arancio O, D'Adamio L. A role for tau in learning, memory and synaptic plasticity. Sci Rep 2018; 8(1): 3184. https://doi.org/10.1038/s41598-018-21596-3.

    • Search Google Scholar
    • Export Citation
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Editor-in-Chief

László ROSIVALL (Semmelweis University, Budapest, Hungary)

Managing Editor

Anna BERHIDI (Semmelweis University, Budapest, Hungary)

Co-Editors

  • Gábor SZÉNÁSI (Semmelweis University, Budapest, Hungary)
  • Ákos KOLLER (Semmelweis University, Budapest, Hungary)
  • Zsolt RADÁK (University of Physical Education, Budapest, Hungary)
  • László LÉNÁRD (University of Pécs, Hungary)
  • Zoltán UNGVÁRI (Semmelweis University, Budapest, Hungary)

Assistant Editors

  • Gabriella DÖRNYEI (Semmelweis University, Budapest, Hungary)
  • Zsuzsanna MIKLÓS (Semmelweis University, Budapest, Hungary)
  • György NÁDASY (Semmelweis University, Budapest, Hungary)

Hungarian Editorial Board

  • György BENEDEK (University of Szeged, Hungary)
  • Zoltán BENYÓ (Semmelweis University, Budapest, Hungary)
  • Mihály BOROS (University of Szeged, Hungary)
  • László CSERNOCH (University of Debrecen, Hungary)
  • Magdolna DANK (Semmelweis University, Budapest, Hungary)
  • László DÉTÁRI (Eötvös Loránd University, Budapest, Hungary)
  • Zoltán GIRICZ (Semmelweis University, Budapest, Hungary and Pharmahungary Group, Szeged, Hungary)
  • Zoltán HANTOS (Semmelweis University, Budapest and University of Szeged, Hungary)
  • Zoltán HEROLD (Semmelweis University, Budapest, Hungary) 
  • László HUNYADI (Semmelweis University, Budapest, Hungary)
  • Gábor JANCSÓ (University of Pécs, Hungary)
  • Zoltán KARÁDI (University of Pecs, Hungary)
  • Miklós PALKOVITS (Semmelweis University, Budapest, Hungary)
  • Gyula PAPP (University of Szeged, Hungary)
  • Gábor PAVLIK (University of Physical Education, Budapest, Hungary)
  • András SPÄT (Semmelweis University, Budapest, Hungary)
  • Gyula SZABÓ (University of Szeged, Hungary)
  • Zoltán SZELÉNYI (University of Pécs, Hungary)
  • Lajos SZOLLÁR (Semmelweis University, Budapest, Hungary)
  • József TOLDI (MTA-SZTE Neuroscience Research Group and University of Szeged, Hungary)
  • Árpád TÓSAKI (University of Debrecen, Hungary)

International Editorial Board

  • Dragan DJURIC (University of Belgrade, Serbia)
  • Christopher H.  FRY (University of Bristol, UK)
  • Stephen E. GREENWALD (Blizard Institute, Barts and Queen Mary University of London, UK)
  • Tibor HORTOBÁGYI (University of Groningen, Netherlands)
  • George KUNOS (National Institutes of Health, Bethesda, USA)
  • Massoud MAHMOUDIAN (Iran University of Medical Sciences, Tehran, Iran)
  • Tadaaki MANO (Gifu University of Medical Science, Japan)
  • Luis Gabriel NAVAR (Tulane University School of Medicine, New Orleans, USA)
  • Hitoo NISHINO (Nagoya City University, Japan)
  • Ole H. PETERSEN (Cardiff University, UK)
  • Ulrich POHL (German Centre for Cardiovascular Research and Ludwig-Maximilians-University, Planegg, Germany)
  • Andrej A. ROMANOVSKY (University of Arizona, USA)
  • Anwar Ali SIDDIQUI (Aga Khan University, Karachi, Pakistan)
  • Csaba SZABÓ (University of Fribourg, Switzerland)
  • Eric VICAUT (Université de Paris, UMRS 942 INSERM, France)

 

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Physiology International
Language English
Size B5
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2006 (1950)
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Founder Magyar Tudományos Akadémia
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