The Role of Serine/Threonine Protein Phosphatases in the Inhibitory Effect of Low Frequency Stimulasion on Perforant Path Kindled Seizure Acquisition

The use of low-frequency electrical stimulation (LFS) as a therapy for epilepsy is currently being studied in experimental animals and patients with epilepsy. In the present study, we investigated the role of serine/threonine protein phosphatases in the inhibitory effects of LFS on perforant path kindling acquisition. Sixty four male Wistar rats were stimulated by perforant path stimulation in a rapid kindling manner (6 stimulations per day). The LFS (1 Hz) was applied immediately after termination of each kindling stimulation. The FK506 (1µM; i.c.v.), a serine/threonine protein phosphatase PP2B inhibitor and okadaic acid (1µM;i.c.v.), a serine/threonine protein phosphatases PP1/2A inhibitor, were daily microinjected into the left ventricle 10 min before starting the stimulation protocol. A two-way ANOVA was done to compare the seizure parameters of different groups. The effect of LFS on behavioral seizure scores was analyzed using the nonparametric Kruskal–Wallis and Mann–Whitney U tests. P value less than 0.05 was considered as the level of significance. Appling LFS immediately after kindling stimulation significantly retarded the kindling acquisition and delayed the expression of different kindled seizure stages. In addition, LFS significantly reduced the increment of daily after-discharge duration during kindling development. (P<0.001) Microinjection of neither FK506 nor okadaic acid had significant effect on the antiepileptogenic effect of LFS on kindling parameters. Our findings showed that activation of PP1/2A and PP2B, which play a critical role in LFS, induced down-regulation of synaptic strength, had no role in mediating the inhibitory effects of LFS on perforant path kindled seizures.