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

J Mol Neurosci. 2019 Feb;67(2):193-203. doi: 10.1007/s12031-018-1224-x. Epub 2018 Nov 29.


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.

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

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Excitatory Postsynaptic Potentials
  • Hippocampus / metabolism*
  • Hippocampus / physiology
  • Long-Term Potentiation*
  • Male
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Rats
  • Rats, Wistar
  • tau Proteins / chemistry
  • tau Proteins / metabolism*


  • tau Proteins
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3