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Long-term depression-related tau phosphorylation is enhanced by methylene blue in healthy rat hippocampus

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Abstract

Background

The present study examined whether inhibition of guanylate cyclase (GC) is associated with the plasticity-related microtubule-stabilizing protein tau phosphorylation in the dentate gyrus (DG) of hippocampal formation.

Methods

To address this issue, methylene blue (MB 50 μM) or saline was infused into the DG starting from the induction of long-term potentiation (LTP) or depression (LTD) for 1 h. Then, protein phosphatase 1 alpha (PP1α), glycogen synthase kinase 3 beta (GSK3β), and tau total and phosphorylated protein levels were measured in these hippocampi using western blotting. LTP and LTD were induced by application of high- and low-frequency stimulation protocols (HFS and LFS), respectively. 5-min averages of the excitatory postsynaptic potential (EPSP) slopes and population spike amplitudes at the end of recording were averaged to measure the magnitude of LTP or LTD.

Results

Low-frequency stimulation protocols was unable to phosphorylate thr181 and thr231epitopes of tau, but possessed kinase activity similar to the HFS in phosphorylation of ser396 and ser416 epitopes. MB infusion during LTD induction attenuated LTD, prevented EPSP/spike dissociation and increased tau phosphorylation at ser396 and ser416 epitopes, without changing tau phosphorylation at thr181 and thr231 epitopes. Neither LTP nor LTP-related tau phosphorylation state was changed by MB infusion.

Conclusion

Although MB can benefit to stabilize the balance between LTP and LTD, and to fix the increased spike wave discharges, it might trigger deregulation of tau phosphorylation, leading to the development of Alzheimer’s disease by a mechanism that goes awry during induction of LTD. Thereby detailed studies to reveal more precise evidence for the use of MB in this disease are needed.

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Acknowledgements

We would like to thank the Erciyes University Research Fund for their financial support under Project Number TYL-2018-8661.

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  1. Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey

    Cem Süer, Nurbanu Yıldız, Özlem Barutçu, Burak Tan & Nurcan Dursun

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  1. Cem Süer
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Contributions

CS: wrote article, analyzing of electrophysiological experiments, feedback of manuscript. NY: electrophysiological experiments, western blot experiments. ÖB: electrophysiological experiments, western blot experiments. BT: western blot experiments, analyzing of western blot images, feedback of manuscript. ND: planning, initiator of project, sectioning, wrote article, feedback of manuscript. All the authors read and approved the manuscript.

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Correspondence to Burak Tan or Nurcan Dursun.

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Süer, C., Yıldız, N., Barutçu, Ö. et al. Long-term depression-related tau phosphorylation is enhanced by methylene blue in healthy rat hippocampus. Pharmacol. Rep 73, 828–840 (2021). https://doi.org/10.1007/s43440-021-00254-y

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