Journal of Molecular Neuroscience

, Volume 67, Issue 2, pp 193–203 | Cite as

Depotentiation of Long-Term Potentiation Is Associated with Epitope-Specific Tau Hyper-/Hypophosphorylation in the Hippocampus of Adult Rats

  • Ercan Babür
  • Burak Tan
  • Sumeyra Delibaş
  • Marwa Yousef
  • Nurcan Dursun
  • Cem SüerEmail author


It is well-known that some kinases which are involved in the induction of synaptic plasticity probably modulate tau phosphorylation. However, how depression of potentiated synaptic strength contributes to tau phosphorylation is unclear because of the lack of experiments in which depotentiation of LTP was induced. Field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded from the dentate gyrus in response to the perforant pathway stimulation. To induce LTP, high-frequency stimulation (HFS) was used, while, for depotentiation of LTP, low-frequency stimulation (LFS) consisting of 900 pulses at 1 Hz was applied 5 min after tetanization. In some experiments, a neutral protocol at 0.033 Hz was applied throughout the experiment without any induction of synaptic plasticity. One-hertz depotentiation protocol was able to decrease fEPSP slope which was previously increased by HFS, whereas no significant change in fEPSP slope and PS amplitude was observed in neutral protocol experiments. Relative to saline infusion, LTP was lower in magnitude and was more reversed by subsequent LFS in the presence of ERK1/2 inhibitor. Western blot experiments indicated that tau protein was hyperphosphorylated at ser416 epitope but rather hypophosphorylated at thr231 epitope in the whole hippocampus upon depotentiation of LTP. These changes concomitantly occurred with a notable increase in the levels of total tau and in the levels of phosphorylated form of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). ERK1/2 inhibition resulted in a decrease in phosphorylation of tau at p416Tau when ERK1/2 was inhibited. These findings indicate that some forms of long-term plastic changes might be related with epitope-specific tau phosphorylation and ERK1/2 activation in the hippocampus. Therefore, we emphasize that tau may be crucial for physiological learning as well as Alzheimer’s disease pathology.


Depotentiation Alzheimer’s disease pathology Extracellular signal-regulated protein kinases 1/2 Tau proteins Hippocampus 


Funding Information

Support was from the Scientific and Technological Research Council of Turkey (TUBITAK) for providing the Student Laboratory Experience Grant. This research was financially supported by Erciyes University Research Found grant number TDK-2016-6628 to C.S.

Compliance with ethical standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12031_2018_1224_MOESM1_ESM.docx (13 kb)
Table 1 Primary antibodies used for Western blot (WB) analysis (DOCX 13 kb)


  1. Akirav I, Richter-Levin G (1999) Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat.. J Neurosci 19:10530–10535Google Scholar
  2. Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K (1994) Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A 91(12):5562–5566Google Scholar
  3. Artis AS, Bitiktas S, Taşkın E, Dolu N, Liman N, Suer C (2012) 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 24(3):422–433Google Scholar
  4. Bolshakov VY, Carboni L, Cobb MH, Siegelbaum SA, Belardetti F (2000) Dual MAP kinase pathways mediate opposing forms of long-term plasticity at CA3-CA1 synapses. Nat Neurosci 3(11):1107–1112Google Scholar
  5. Chen Q, Zhou Z, Zhang L, Wang Y, Zhang YW, Zhong M, Xu SC, Chen CH, Li L, Yu ZP (2012) Tau protein is involved in morphological plasticity in hippocampal neurons in response to BDNF. Neurochem Int 60(3):233–242Google Scholar
  6. Colbert CM, Levy WB (1993) Long-term potentiation of perforant path synapses in hippocampal CA1 in vitro. Brain Res 606(1):87–91Google Scholar
  7. Correa SA, Eales KL (2012) The role of p38 MAPK and its substrates in neuronal plasticity and neurodegenerative disease. J Signal Transduct 2012:649079Google Scholar
  8. Doble BW, Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116(Pt 7):1175–1186Google Scholar
  9. Drewes G, Lichtenberg-Kraag B, Döring F, Mandelkow EM, Biernat J, Goris J, Dorée M, Mandelkow E (1992) Mitogen activated protein (map) kinase transforms tau-protein into an Alzheimer-like state. EMBO J 11(6):2131–2138Google Scholar
  10. Fleming LM, Johnson GV (1995) Modulation of the phosphorylation state of tau in situ: the roles of calcium and cyclic AMP. Biochem J 309(Pt 1):41–47Google Scholar
  11. Frandemiche ML, de Seranno S, Rush T, Borel E, Elie A, Arnal I, Lante F, Buisson A (2014) Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-Beta oligomers. J Neurosci 34(17):6084–6097Google Scholar
  12. Fujii S, Sekino Y, Kuroda Y, Sasaki H, Ito KI, Kato H (1997) 8-cyclopentyltheophylline, an adenosine A1 receptor antagonist, inhibits the reversal of long-term potentiation in hippocampal CA1 neurons. Eur J Pharmacol 331(1):9–14Google Scholar
  13. Fukunaga K, Muller D, Miyamoto E (1996) CaM kinase II in long-term potentiation. Neurochem Int 28(4):343–358Google Scholar
  14. Garver TD, Kincaid RL, Conn RA, Billingsley ML (1999) Reduction of calcineurin activity in brain by antisense oligonucleotides leads to persistent phosphorylation of tau protein at Thr(181) and Thr(231). Mol Pharmacol 55(4):632–641Google Scholar
  15. Goedert M, Jakes R, Qi Z, Wang JH, Cohen P (1995) Protein phosphatase 2A is the major enzyme in brain that dephosphorylates τ protein phosphorylated by proline-directed protein kinases or cyclic AMP-dependent protein kinase. J Neurochem 65(6):2804–2807Google Scholar
  16. Golding NL, N.P. Staff, Spruston N (2002) Dendritic spikes as a mechanism for cooperative long-term potentiation. Nature 418(6895):326–331Google Scholar
  17. Gomez-Ramos A et al (2004) Tau phosphorylation and assembly. Acta Neurobiol Exp (Wars) 64(1):33–39Google Scholar
  18. Greene JG, Borges K, Dingledine R (2009) Quantitative transcriptional neuroanatomy of the rat hippocampus: evidence for wide-ranging, pathway-specific heterogeneity among three principal cell layers. Hippocampus 19(3):253–264Google Scholar
  19. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83(13):4913–4917Google Scholar
  20. Hashiguchi M, Saito T, Hisanaga SI, Hashiguchi T (2002) Truncation of CDK5 activator p35 induces intensive phosphorylation of Ser202/Thr205 of human tau. J Biol Chem 277(46):44525–44530Google Scholar
  21. Huang CC, Liang YC, Hsu KS (1999) A role for extracellular adenosine in time-dependent reversal of long-term potentiation by low-frequency stimulation at hippocampal CA1 synapses. J Neurosci 19(22):9728–9738Google Scholar
  22. Iqbal K, del C. Alonso A, Chen S, Chohan MO, el-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739(2–3):198–210Google Scholar
  23. Ittner LM, Gotz J (2011) Amyloid-beta and tau—a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci 12(2):65–72Google Scholar
  24. Kang-Park MH, Sarda MA, Jones KH, Moore SD, Shenolikar S, Clark S, Wilson WA (2003) Protein phosphatases mediate depotentiation induced by high-intensity theta-burst stimulation. J Neurophysiol 89(2):684–690Google Scholar
  25. Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S, Brown C, Hashikawa T, Murayama M, Seok H, Sotiropoulos I, Kim E, Collingridge GL, Takashima A, Cho K (2014) Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Philos Trans R Soc B 369:20130144Google Scholar
  26. Kins S, Kurosinski P, Nitsch RM, Götz J (2003) Activation of the ERK and JNK signaling pathways caused by neuron-specific inhibition of PP2A in transgenic mice. Am J Pathol 163(3):833–843Google Scholar
  27. Kobayashi S, Tanaka T, Soeda Y, Almeida OFX, Takashima A (2017) Local Somatodendritic translation and hyperphosphorylation of tau protein triggered by AMPA and NMDA receptor stimulation. Ebiomedicine 20:120–126Google Scholar
  28. Kopke E et al (1993) Microtubule-associated protein-tau—abnormal phosphorylation of a non-paired helical filament pool in Alzheimer-disease. J Biol Chem 268(32):24374–24384Google Scholar
  29. Krapivinsky G, Medina I, Krapivinsky L, Gapon S, Clapham DE (2004) SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation. Neuron 43(4):563–574Google Scholar
  30. Liang YC, Huang CC, Hsu KS (2008) A role of p38 mitogen-activated protein kinase in adenosine A(1) receptor-mediated synaptic depotentiation in area CA1 of the rat hippocampus. Mol Brain 1:13Google Scholar
  31. Liu J, Fukunaga K, Yamamoto H, Nishi K, Miyamoto E (1999) Differential roles of Ca2+/calmodulin-dependent protein kinase II and mitogen-activated protein kinase activation in hippocampal long-term potentiation. J Neurosci 19(19):8292–8299Google Scholar
  32. Mondragon-Rodriguez S et al (2012) Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem 287(38):32040–32053Google Scholar
  33. Morris M, Maeda S, Vossel K, Mucke L (2011) The many faces of tau. Neuron 70(3):410–426Google Scholar
  34. Moult PR, Corrêa SAL, Collingridge GL, Fitzjohn SM, Bashir ZI (2008) Co-activation of p38 mitogen-activated protein kinase and protein tyrosine phosphatase underlies metabotropic glutamate receptor-dependent long-term depression. J Physiol 586(10):2499–2510Google Scholar
  35. O'Dell TJ, Kandel ER (1994) Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases. Learn Mem 1(2):129–139Google Scholar
  36. O’reilly RC, Norman KA, McClelland JL (1998) A hippocampal model of recognition memory. In: Advances in neural information processing systems, pp 73–79Google Scholar
  37. Pei JJ, Gong CX, An WL, Winblad B, Cowburn RF, Grundke-Iqbal I, Iqbal K (2003) Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK-1/2, and p70 S6, similar to that in Alzheimer’s disease. Am J Pathol 163(3):845–858Google Scholar
  38. Peng S, Zhang Y, Zhang J, Wang H, Ren B (2010) ERK in learning and memory: a review of recent research. Int J Mol Sci 11(1):222–232Google Scholar
  39. Racaniello M, Cardinale A, Mollinari C, D’Antuono M, de Chiara G, Tancredi V, Merlo D (2010) Phosphorylation changes of CaMKII, ERK1/2, PKB/Akt kinases and CREB activation during early long-term potentiation at Schaffer collateral-CA1 mouse hippocampal synapses. Neurochem Res 35(2):239–246Google Scholar
  40. Regan P, Piers T, Yi JH, Kim DH, Huh S, Park SJ, Ryu JH, Whitcomb DJ, Cho K (2015) Tau phosphorylation at serine 396 residue is required for hippocampal LTD. J Neurosci 35(12):4804–4812Google Scholar
  41. Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels JL, Mucke L (2011) Amyloid-beta/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci 31(2):700–711Google Scholar
  42. Schmitt JM, Wayman GA, Nozaki N, Soderling TR (2004) Calcium activation of ERK mediated by calmodulin kinase I. J Biol Chem 279(23):24064–24072Google Scholar
  43. Shipton OA, Leitz JR, Dworzak J, Acton CEJ, Tunbridge EM, Denk F, Dawson HN, Vitek MP, Wade-Martins R, Paulsen O, Vargas-Caballero M (2011) Tau protein is required for amyloid beta-induced impairment of hippocampal long-term potentiation. J Neurosci 31(5):1688–1692Google Scholar
  44. Steiner B, Mandelkow EM, Biernat J, Gustke N, Meyer HE, Schmidt B, Mieskes G, Söling HD, Drechsel D, Kirschner MW, Goedert M, Mandelkow E (1990) Phosphorylation of microtubule-associated protein tau: identification of the site for Ca2(+)-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles. EMBO J 9(11):3539–3544Google Scholar
  45. Suer C, Dolu N, Artis AS, Sahin L, Aydogan S (2011) Electrophysiological evidence of biphasic action of carnosine on long-term potentiation in urethane-anesthetized rats. Neuropeptides 45(1):77–81Google Scholar
  46. Thomas GM, Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5(3):173–183Google Scholar
  47. Tian Q, Wang J (2002) Role of serine/threonine protein phosphatase in Alzheimer’s disease. Neurosignals 11(5):262–269Google Scholar
  48. Wang JZ, Grundke-Iqbal I, Iqbal K (2007) Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25(1):59–68Google Scholar
  49. Yamamoto H, Saitoh Y, Fukunaga K, Nishimura H, Miyamoto E (1988) Dephosphorylation of microtubule proteins by brain protein phosphatases 1 and 2A, and its effect on microtubule assembly. J Neurochem 50(5):1614–1623Google Scholar
  50. Yamamoto H, Hiragami Y, Murayama M, Ishizuka K, Kawahara M, Takashima A (2005) Phosphorylation of tau at serine 416 by Ca2+/calmodulin-dependent protein kinase II in neuronal soma in brain. J Neurochem 94(5):1438–1447Google Scholar
  51. Yang Q, Zhu G, Liu D, Ju J-G, Liao Z-H, Xiao Y-X, Zhang Y, Chao N, Wang J, Li W (2017) Extrasynaptic NMDA receptor dependent long-term potentiation of hippocampal CA1 pyramidal neurons. Sci Rep 7:3045. Accessed 22 Sept 2018
  52. Yeckel MF, Berger TW (1990) Feedforward excitation of the hippocampus by afferents from the entorhinal cortex—redefinition of the role of the trisynaptic pathway. Proc Natl Acad Sci U S A 87(15):5832–5836Google Scholar
  53. Zhang YH, Wang DW, Xu SF, Zhang S, Fan YG, Yang YY, Guo SQ, Wang S, Guo T, Wang ZY, Guo C (2018) Alpha-lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S tau transgenic mice. Redox Biol 14:535–548Google Scholar
  54. Zhu X, Rottkamp CA, Boux H, Takeda A, Perry G, Smith MA (2000) Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J Neuropathol Exp Neurol 59(10):880–888Google Scholar
  55. Zhu Y, Pak D, Qin Y, McCormack SG, Kim MJ, Baumgart JP, Velamoor V, Auberson YP, Osten P, van Aelst L, Sheng M, Zhu JJ (2005) Rap2-JNK removes synaptic AMPA receptors during depotentiation. Neuron 46(6):905–916Google Scholar
  56. Zhuo M, Zhang W, Son H, Mansuy I, Sobel RA, Seidman J, Kandel ER (1999) A selective role of calcineurin aalpha in synaptic depotentiation in hippocampus. Proc Natl Acad Sci U S A 96(8):4650–4655Google Scholar

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Authors and Affiliations

  1. 1.Department of PhysiologyMedical School of Erciyes UniversityKayseriTurkey
  2. 2.Department of Physiology Faculty of MedicineErciyes UniversityKayseriTurkey

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