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.
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): 11117–27. https://doi.org/10.1021/bi00035a017.
Ittner A, Ittner LM. Dendritic tau in Alzheimer's disease. Neuron 2018; 99(1): 13–27. https://doi.org/10.1016/j.neuron.2018.06.003.
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): 4804–12. https://doi.org/10.1523/JNEUROSCI.2842-14.2015.
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.
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): 193–203. https://doi.org/10.1007/s12031-018-1224-x.
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): 577–91. https://doi.org/10.1042/bj3230577.
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): 198–210. https://doi.org/10.1016/j.bbadis.2004.09.008.
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): 4913–7. https://doi.org/10.1073/pnas.83.13.4913.
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): 5562–6. https://doi.org/10.1073/pnas.91.12.5562.
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.
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): 3319–29. https://doi.org/10.1523/JNEUROSCI.4521-14.2015.
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): 422–33. https://doi.org/10.1111/j.1365-2826.2011.02253.x.
Impey S, Obrietan K, Storm DR. Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 1999; 23(1): 11–4. https://doi.org/10.1016/s0896-6273(00)80747-3.
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): 498–511. https://doi.org/10.1016/j.neuron.2011.06.011.
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): 1107–12. https://doi.org/10.1038/80624.
Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell 2000; 103(2): 239–52. https://doi.org/10.1016/s0092-8674(00)00116-1.
Lai KO, Ip NY. Recent advances in understanding the roles of Cdk5 in synaptic plasticity. Biochim Biophys Acta 2009; 1792(8): 741–5. https://doi.org/10.1016/j.bbadis.2009.05.001.
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): 519–26. https://doi.org/10.1016/0896-6273(89)90210-9.
Andreadis A, Brown WM, Kosik KS. Structure and novel exons of the human tau gene. Biochemistry 1992; 31(43): 10626–33. https://doi.org/10.1021/bi00158a027.
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): 4051–5. https://doi.org/10.1073/pnas.85.11.4051.
Taube JS, Schwartzkroin PA. Mechanisms of long-term potentiation: EPSP/spike dissociation, intradendritic recordings, and glutamate sensitivity. J Neurosci 1988; 8(5): 1632–44. https://doi.org/10.1523/JNEUROSCI.08-05-01632.1988.
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): 58–64. https://doi.org/10.1016/0304-3940(89)90329-7.
Zucker RS. Calcium- and activity-dependent synaptic plasticity. Curr Opin Neurobiol 1999; 9(3): 305–13. https://doi.org/10.1016/s0959-4388(99)80045-2.
Evans RC, Blackwell KT. Calcium: amplitude, duration, or location? Biol Bull 2015; 228(1): 75–83. https://doi.org/10.1086/BBLv228n1p75.
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): 5382–92. https://doi.org/10.1523/JNEUROSCI.16-17-05382.1996.
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): 1627–37. https://doi.org/10.1007/s00221-021-06090-z.
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.
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): 7221–31. https://doi.org/10.1523/JNEUROSCI.0909-05.2005.
Frey U, Morris RG. Synaptic tagging and long-term potentiation. Nature 1997; 385(6616): 533–6. https://doi.org/10.1038/385533a0.
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.
Christie BR, Stellwagen D, Abraham WC. Reduction of the threshold for long-term potentiation by prior theta-frequency synaptic activity. Hippocampus 1995; 5(1): 52–9. https://doi.org/10.1002/hipo.450050107.
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): 239–45. https://doi.org/10.1016/j.neuron.2006.08.015.
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.
Fioravante D, Byrne JH. Protein degradation and memory formation. Brain Res Bull 2011; 85(1–2): 14–20. https://doi.org/10.1016/j.brainresbull.2010.11.002.
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): 283–93. https://doi.org/10.1074/mcp.M600046-MCP200.
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): 684–96. https://doi.org/10.1074/mcp.M700170-MCP200.
Westenbroek RE, Merrick DK, Catterall WA. Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons. Neuron 1989; 3(6): 695–704. https://doi.org/10.1016/0896-6273(89)90238-9.
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): 832–44. https://doi.org/10.1016/j.bbagen.2015.01.011.
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): 273–9. https://doi.org/10.1016/j.expneurol.2011.05.005.
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): 803–8. https://doi.org/10.1002/j.1460-2075.1993.tb05715.x.
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): 703–17. https://doi.org/10.1016/j.neuron.2007.01.029.
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): 39–49. https://doi.org/10.1016/j.arr.2012.06.008.
Mansuy IM, Shenolikar S. Protein serine/threonine phosphatases in neuronal plasticity and disorders of learning and memory. Trends Neurosci 2006; 29(12): 679–86. https://doi.org/10.1016/j.tins.2006.10.004.
Foley K, McKee C, Nairn AC, Xia H. Regulation of synaptic Transmission and plasticity by protein phosphatase 1. J Neurosci 2021; 41(14): 3040–50. https://doi.org/10.1523/JNEUROSCI.2026-20.2021.
Mulkey RM, Herron CE, Malenka RC. An essential role for protein phosphatases in hippocampal long-term depression. Science 1993; 261(5124): 1051–5. https://doi.org/10.1126/science.8394601.
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): 1093–104. https://doi.org/10.1002/hipo.20823.
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): 32040–53. https://doi.org/10.1074/jbc.M112.401240.
Medeiros R, Baglietto-Vargas D, LaFerla FM. The role of tau in Alzheimer's disease and related disorders. CNS Neurosci Ther 2011; 17(5): 514–24. https://doi.org/10.1111/j.1755-5949.2010.00177.x.
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.