Skip to main content

N-methyl-d-aspartate receptor blockade reduces plasticity-related tau expression and phosphorylation of tau at Ser416 residue but not Thr231 residue

Abstract

The molecular mechanisms regulating N-methyl-d-aspartate (NMDA) receptor-dependent synaptic plasticity are complex, and the contribution of Tau protein in the physiological process is not fully understood. Herein, we investigated whether the blockade of NMDA receptor activation might change Tau phosphorylation during long-term potentiation (LTP) and long-term depression (LTD) via contribution of GSK3β as a major Tau kinase. For this, we recorded two components (synaptic and population spike components) of hippocampal field potential, which is evoked by the stimulation of the perforant pathway with high- and low-frequency stimulation (HFS and LFS). We found under a 20-µl volume of D-AP5 infusion lasting 1 h that,HFS caused significant synaptic depression, whereas LFS induced a synaptic potentiation. Both the HFS and LFS protocols resulted in a significant increase in population spike component but were characterized by a slow increase in amplitude that occurred with the LFS. D-AP5 attenuated HFS-induced population spike potentiation, but augmented LFS-induced population spike potentiation. The enzymatic activity of GSK-3β was decreased by D-AP5 infusion in the hippocampus, indicating that NMDA receptor activity modulates the enzymatic activity of GSK-3β. In addition, NMDA receptor blockade reduced tau expression and phosphorylation of tau at Ser416 residue, but not Thr231 residue. These findings confirm previous studies that D-AP5 applied to the DG in vivo blocks HFS-induced LTP, but we further also showed that the same dose of D-AP5 resulted in a slowly rising LFS-induced LTP and HFS-induced LTD. The formation of such an LTP, together with reduced enzymatic activity of GSK-3β and tau phosphorylation at Ser416 epitope, can make it a candidate mechanism for prevention of taupathies.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Aceto G et al (2019) GSK3 beta modulates timing-dependent long-term depression through direct phosphorylation of Kv4.2 channels (vol 18, bhy042, 2019). Cereb Cortex 29(12):5315–5315

    PubMed  PubMed Central  Google Scholar 

  2. Alonso ADC et al (2001) Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci 98(12):6923–6928

    CAS  PubMed  Google Scholar 

  3. Anand R, Gill KD, Mahdi AA (2014) Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology 76:27–50

    CAS  PubMed  Google Scholar 

  4. Artis AS et al (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):422–433

    CAS  PubMed  Google Scholar 

  5. Augustinack JC et al (2002) Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol 103(1):26–35

    CAS  PubMed  Google Scholar 

  6. Babür E et al (2019) Deficiency but not supplementation of selenium impairs the hippocampal long-term potentiation and hippocampus-dependent learning. Biol Trace Element Res 192:1–11

    Google Scholar 

  7. Baird DH, Trenkner E, Mason CA (1996) Arrest of afferent axon extension by target neurons in vitro is regulated by the NMDA receptor. J Neurosci 16(8):2642–2648

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Balu DT (2016) The NMDA receptor and schizophrenia: from pathophysiology to treatment. In: Neuropsychopharmacol tribute to Joseph T. Coyle, vol 76. pp 351–382

  9. Beck H et al (2000) Synaptic plasticity in the human dentate gyrus. J Neurosci 20(18):7080–7086

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bitiktaş S et al (2016) Effects of selenium treatment on 6-n-propyl-2-thiouracil-induced impairment of long-term potentiation. Neurosci Res 109:70–76

    PubMed  Google Scholar 

  11. Bitiktaş S et al (2017) The effects of intra-hippocampal l-thyroxine infusion on long-term potentiation and long-term depression: a possible role for the αvβ3 integrin receptor. J Neurosci Res 95(8):1621–1632

    PubMed  Google Scholar 

  12. Blaise JH, Bronzino JD (2003) Effects of stimulus frequency and age on bidirectional synaptic plasticity in the dentate gyrus of freely moving rats. Exp Neurol 182(2):497–506

    PubMed  Google Scholar 

  13. Bloom GS (2014) Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71(4):505–508

    PubMed  Google Scholar 

  14. Busciglio J et al (1995) β-Amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14(4):879–888

    CAS  PubMed  Google Scholar 

  15. Castillo PE (2012) Presynaptic LTP and LTD of excitatory and inhibitory synapses. Cold Spring Harb Perspect Biol 4(2):a005728

    PubMed  PubMed Central  Google Scholar 

  16. Chavez-Noriega L, Halliwell J, Bliss T (1990) A decrease in firing threshold observed after induction of the EPSP-spike (ES) component of long-term potentiation in rat hippocampal slices. Exp Brain Res 79(3):633–641

    CAS  PubMed  Google Scholar 

  17. Cohen AS et al (1999) Long-lasting increase in cellular excitability associated with the priming of LTP induction in rat hippocampus. J Neurophysiol 82(6):3139–3148

    CAS  PubMed  Google Scholar 

  18. Collingridge GL et al (2010) Long-term depression in the CNS. Nat Rev Neurosci 11(7):459–473

    CAS  PubMed  Google Scholar 

  19. de Bartolomeis A et al (2013) Different effects of the NMDA receptor antagonists ketamine, MK-801, and memantine on postsynaptic density transcripts and their topography: role of Homer signaling, and implications for novel antipsychotic and pro-cognitive targets in psychosis. Prog Neuropsychopharmacol Biol Psychiatry 46:1–12

    PubMed  Google Scholar 

  20. De Montigny A et al (2013a) NMDA reduces tau phosphorylation in rat hippocampal slices by targeting NR2A receptors, GSK3 beta, and PKC activities. Neural Plast 2013:1–10

    Google Scholar 

  21. De Montigny A et al (2013b) NMDA reduces Tau phosphorylation in rat hippocampal slices by targeting NR2A receptors, GSK3β, and PKC activities. Neural Plast 2013:1–10

    Google Scholar 

  22. Desmond NL, Colbert CM, Levy WB (1991) NMDA receptor antagonists block the induction of long-term depression in the hippocampal dentate gyrus of the anesthetized rat. Brain Res 552(1):93–98

    CAS  PubMed  Google Scholar 

  23. Farber NB, Newcomer JW, Olney JW (1998) The glutamate synapse in neuropsychiatric disorders: focus on schizophrenia and Alzheimer’s disease. Progress in brain research. Elsevier, pp 421–437

    Google Scholar 

  24. Fleming LM, Johnson GVW (1995) Modulation of the phosphorylation state of tau in-situ—the roles of calcium and cyclic-Amp. Biochem J 309:41–47

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gardoni F et al (2009) Decreased NR2B subunit synaptic levels cause impaired long-term potentiation but not long-term depression. J Neurosci 29(3):669–677

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Grover LM, Teyler TJ (1990) Two components of long-term potentiation induced by different patterns of afferent activation. Nature 347(6292):477–479

    CAS  PubMed  Google Scholar 

  27. Gustke N et al (1992) The Alzheimer-like phosphorylation of tau protein reduces microtubule binding and involves Ser-Pro and Thr-Pro motifs. FEBS Lett 307(2):199–205

    CAS  PubMed  Google Scholar 

  28. Harney SC, Rowan M, Anwyl R (2006) Long-term depression of NMDA receptor-mediated synaptic transmission is dependent on activation of metabotropic glutamate receptors and is altered to long-term potentiation by low intracellular calcium buffering. J Neurosci 26(4):1128–1132

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hawasli AH et al (2007) Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat Neurosci 10(7):880

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hirokawa N et al (1996) Selective stabilization of tau in axons and microtubule-associated protein 2C in cell bodies and dendrites contributes to polarized localization of cytoskeletal proteins in mature neurons. J Cell Biol 132(4):667–679

    CAS  PubMed  Google Scholar 

  31. Hooper C et al (2007) Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur J Neurosci 25(1):81–86

    PubMed  Google Scholar 

  32. Huang Y-J et al (2012) NMDA neurotransmission dysfunction in behavioral and psychological symptoms of Alzheimer’s disease. Curr Neuropharmacol 10(3):272–285

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Huber KM, Mauk MD, Kelly PT (1995) Distinct LTP induction mechanisms: contribution of NMDA receptors and voltage-dependent calcium channels. J Neurophysiol 73(1):270–279

    CAS  PubMed  Google Scholar 

  34. Ishikawa M et al (2009) Homeostatic synapse-driven membrane plasticity in nucleus accumbens neurons. J Neurosci 29(18):5820–5831

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kapitein LC et al (2011) NMDA receptor activation suppresses microtubule growth and spine entry. J Neurosci 31(22):8194–8209

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kauderer BS, Kandel ER (2000) Capture of a protein synthesis-dependent component of long-term depression. Proc Natl Acad Sci 97(24):13342–13347

    CAS  PubMed  Google Scholar 

  37. Kemp N et al (2000a) Different forms of LTD in the CA1 region of the hippocampus: role of age and stimulus protocol. Eur J Neurosci 12(1):360–366

    CAS  PubMed  Google Scholar 

  38. Lee H-K et al (1998) NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21(5):1151–1162

    CAS  PubMed  Google Scholar 

  39. Lüscher C, Malenka RC (2012) NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb Perspect Biol 4(6):a005710

    PubMed  PubMed Central  Google Scholar 

  40. Massey PV, Bashir ZI (2007) Long-term depression: multiple forms and implications for brain function. Trends Neurosci 30(4):176–184

    CAS  PubMed  Google Scholar 

  41. Massey PV et al (2004) Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J Neurosci 24(36):7821–7828

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Mondragon-Rodriguez S, Burgeois C, Boehm J (2011) Tau phosphorylation links Amyloid beta and NMDA receptor activation, implications for Alzheimer’s disease. Alzheimer’s Dement J Alzheimer’s Assoc 7(4):e23–e24

    Google Scholar 

  43. Moon RT et al (2004) WNT and β-catenin signalling: diseases and therapies. Nat Rev Genet 5(9):691

    CAS  PubMed  Google Scholar 

  44. Muller T, Albrecht D, Gebhardt C (2009) Both NR2A and NR2B subunits of the NMDA receptor are critical for long-term potentiation and long-term depression in the lateral amygdala of horizontal slices of adult mice. Learn Mem 16(6):395–405

    PubMed  Google Scholar 

  45. Naini SMA, Soussi-Yanicostas N (2015) Tau hyperphosphorylation and oxidative stress, a critical vicious circle in neurodegenerative tauopathies? Oxid Med Cell Longev 2015:1–17

    Google Scholar 

  46. Newcomer JW, Farber NB, Olney JW (2000) NMDA receptor function, memory, and brain aging. Dialog Clin Neurosci 2(3):219

    CAS  Google Scholar 

  47. Norris CM, Korol DL, Foster TC (1996) Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging. J Neurosci 16(17):5382–5392

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Pagadala P et al (2013) Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: involvement of Ca2+-activated small conductance potassium channels. J Neurosci 33(33):13425–13430

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Peineau S et al (2007) LTP inhibits LTD in the hippocampus via regulation of GSK3β. Neuron 53(5):703–717

    CAS  PubMed  Google Scholar 

  50. Peineau S et al (2008) The role of GSK-3 in synaptic plasticity. Br J Pharmacol 153(S1):S428–S437

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Regan P et al (2015) Tau phosphorylation at serine 396 residue is required for hippocampal LTD. J Neurosci 35(12):4804–4812

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Rothman SM, Olney JW (1986) Glutamate and the pathophysiology of hypoxic–ischemic brain damage. Ann Neurol 19(2):105–111

    CAS  PubMed  Google Scholar 

  53. Sah P, Hestrin S, Nicoll RA (1989) Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons. Science 246(4931):815–818

    CAS  PubMed  Google Scholar 

  54. Shin R et al (1991) Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer’s disease brain tissues. Lab Investig J Tech Methods Pathol 64(5):693–702

    CAS  Google Scholar 

  55. Stanton PK, Sejnowski TJ (1989) Associative long-term depression in the hippocampus induced by hebbian covariance. Nature 339(6221):215–218

    CAS  PubMed  Google Scholar 

  56. Sun X-Y et al (2016) Extrasynaptic NMDA receptor-induced tau overexpression mediates neuronal death through suppressing survival signaling ERK phosphorylation. Cell Death Dis 7(11):e2449

    PubMed  PubMed Central  Google Scholar 

  57. Tang Y-P et al (1999) Genetic enhancement of learning and memory in mice. Nature 401(6748):63

    CAS  PubMed  Google Scholar 

  58. Trommer BL et al (1995) AP5 blocks LTP in developing rat dentate gyrus and unmasks LTD. Exp Neurol 131(1):83–92

    CAS  PubMed  Google Scholar 

  59. Wang Q et al (2007) Developmental dependence, the role of the kinases p38 MAPK and PKC, and the involvement of tumor necrosis factor-R1 in the induction of mGlu-5 LTD in the dentate gyrus. Neuroscience 144(1):110–118

    CAS  PubMed  Google Scholar 

  60. Wong TP et al (2007) Hippocampal long-term depression mediates acute stress-induced spatial memory retrieval impairment. Proc Natl Acad Sci 104(27):11471–11476

    CAS  PubMed  Google Scholar 

  61. Zhang Y et al (2016) Dysfunction of NMDA receptors in Alzheimer’s disease. Neurol Sci 37(7):1039–1047

    PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was funded by The Research Foundation of Erciyes University of Turkey (Grant number: TDK-2016–6628). Authors Burak Tan, Ezgi Aslan Gülpınar, Nurcan Dursun, Cem Süer were received research Grants from Erciyes University, School of Medicine, Department of Physiology.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Burak Tan.

Ethics declarations

Conflict of interest

Authors Burak Tan declares that he has no conflict of interest. Author Ezgi Aslan Gülpınar declares that she has no conflict of interest. Author Nurcan Dursun declares that she has no conflict of interest. Author Cem Süer declares that he has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Communicated by Sreedharan Sajikumar.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tan, B., Aslan-Gülpınar, E., Dursun, N. et al. 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 239, 1627–1637 (2021). https://doi.org/10.1007/s00221-021-06090-z

Download citation

Keywords

  • Synaptic plasticity
  • Long-term potentiation
  • Long-term depression
  • AP5
  • Tau
  • GSK3β