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 mu M) 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 (PP1 alpha), glycogen synthase kinase 3 beta (GSK3 beta), 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 thr(181) and thr(231)epitopes of tau, but possessed kinase activity similar to the HFS in phosphorylation of ser(396) and ser(416) epitopes. MB infusion during LTD induction attenuated LTD, prevented EPSP/spike dissociation and increased tau phosphorylation at ser(396) and ser(416) epitopes, without changing tau phosphorylation at thr(181) and thr(231) 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.