Wistar. Kruskal-Wallis Whitney. 1-3Hz. in vitro. (Depotentiation) LFS LFS LFS LFS LFS PP1/2A LFS (PP1/2A, PP2B)

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1 Wistar Mann- Kruskal-Wallis P< Whitney P< (, ) 1-3Hz in vitro (Depotentiation) 1 Low-frequency Stimulation 2 Long-term Depression sadegh.mehdi@gmail.com

2 icv (Paired-pulse depression) Wistar LTP LTP PPs mg/kg LTP Paxinos Watson G 3 Long-term potentiation

3 Differential Earth Rapid kindling pepsp pepsp G Daily ADD Fluka Sigma-Aldrich DMSO ph HCl ph DMSO ph PE-20 5 After Discharge Duration 4 Population Excitory Post-Syaptic plasticity

4 G ( Stoelting DMSO Okadaic Kindled++ M acid Microsyring Pump) Stoelting Mean±S.E.M l min Kolmogrove-Smirnove LSD Repeated Measures Hz Kindled Mann- Kruskal-Wallis Kindled+ Two Whitney P< tailed Kindled+DMSO DMSO ADD DMSO Kindled++DMSO ± Kindled Kindled+ Kindled+ ± M Kindled++ Kindled+

5 Repeated LSD Measures Kindled+ DMSO Kindled+DMSO Kindled P< ADD Mann-Withney Kindled++DMSO Kindled+ Repeated Measures P< Kindled LSD Kindled++ Kindled++DMSO Kruskal-Wallis Kindled++ Kindled++DMSO Kindled+Okadaic Kindled+DMSO acid Kindled++ Repeated Measures Mann-Whitney LSD Mean±S.E.M Kindled++DMSO n = 6 Least Significant Difference

6 Focal seizure Generalized seizure Daily Afterdischarge Duration LSD Repeated Measures (After discharge Kruskal-Wallis n = Mean±S.E.M Threshold) Hz

7 LTP LTP LTP icv NMDA NMDA. NMDA NMDA CA1

8 References 1. Fujii H, Hirano T. Calcineurin regulates induction of late phase of cerebellar long-term depression in rat cultured Purkinje neurons. Eur J Neurosci. 2002; 16: Fujii S, Kuroda Y, Ito KL, et al. Endogenous adenosine regulates the effects of lowfrequency stimulation on the induction of long-term potentiation in CA1 neurons of guinea pig hippocampal slices. Neurosci Lett. 2000; 279: Klausnitzer J, Kulla A, Manahan-Vaughan D. Role of the group III metabotropic glutamate receptor in LTP, depotentiation and in dentate gyrus of freely moving rats. Neuropharmacology. 2004; 46: Manahan-Vaughan D, Kulla A. Regulation of depotentiation and long-term potentiation in the dentate gyrus of freely moving rats by dopamine D2-like receptors. Cereb Cortex. 2003; 13: Gaito J. The effect of low frequency and direct current stimulation on the kindling phenomenon in rats. Can J Neurol Sci. 1981;249; Goodman JH, Berger RE, Tcheng TK. Preemptive low-frequency stimulation decreases the incidence of amygdala-kindled seizures. Epilepsia. 2005; 46: Yang LX, Jin CL, Zhu-Ge ZB, et al. Unilateral low-frequency stimulation of central piriform cortex delays seizure development induced by amygdaloid kindling in rats. Neuroscience. 2006; 138: Sadegh M, Mirnajafi-Zadeh J, Javan M, et al. The role of galanin receptors in anticonvulsant effects of low-frequency stimulation in perforant path-kindled rats. Neuroscience. 2007; 150: Mohammad-Zadeh M, Mirnajafi-Zadeh J, Fathollahi Y, et al. Effect of low frequency stimulation of perforant path on kindling rate and synaptic transmission in the dentate gyrus during kindling acquisition in rats. Epilepsy Res. 2007; 75: Oliet SH, Malenka RC, Nicoll RA. Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells. Neuron. 1997; 18: Scharfman HE. Epilepsy as an example of neural plasticity. Neuroscientist 2002; 8: Malenka RC, Kauer JA, Perkel DJ, et al. An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature. 1989; 340:

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10 28. Yamamoto J, Ikeda A, Satow T, et al. Low-frequency electric cortical stimulation has an inhibitory effect on epileptic focus in mesial temporal lobe epilepsy. Epilepsia. 2002; 43: Lopez-Meraz ML, Neri-Bazan L, Rocha L. Low frequency stimulation modifies receptor binding in rat brain. Epilepsy Res. 2004; 59: Ghorbani P, Mohammad-Zadeh M, Mirnajafi-Zadeh J, et al. Effect of different patterns of low-frequency stimulation on piriform cortex kindled seizures. Neurosci Lett. 2007; 425: Abraham WC, Mason-Parker SE, Logan B. Low-frequency stimulation does not readily cause long-term depression or depotentiation in the dentate gyrus of awake rats. Brain Res. 1996; 722: Lin CH, Lee CC, Gean PW. Involvement of a calcineurin cascade in amygdala depotentiation and quenching of fear memory. Mol Pharmacol. 2003; 63: Morimoto K, Fahnestock M, Racine RJ. Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog Neurobiol. 2004; 73: Sloviter RS. The neurobiology of temporal lobe epilepsy too much information, not enough knowledge. C R Biol. 2005; 328: Jouvenceau A, Billard JM, Haditsch U, et al. Different phosphatase-dependent mechanisms mediate long-term depression and depotentiation of long-term potentiation in mouse hippocampal CA1 area. Eur J Neurosci. 2003; 18: Solger J, Wozny C, Manahan-Vaughan D, et al. Distinct mechanisms of bidirectional activity-dependent synaptic plasticity in superficial and deep layers of rat entorhinal cortex. Eur J Neurosci. 2004; 19: Wang YT, Yu XM, Salter MW. Ca 2+ -independent reduction of N-methyl-D-aspartate channel activity by protein tyrosine phosphatase. Proc Natl Acad Sci USA. 1996; 93: Schrader LM, Stern JM, Wilson CL, et al. Low frequency electrical stimulation through subdural electrodes in a case of refractory status epilepticus. Clin Neurophysiol. 2006; 117:781-7

11 The Role of Serine/Threonine Protein Phosphatases in the Inhibitory Effect of Low Frequency Stimulasion on Perforant Path Kindled Seizure Acquisition Sadegh Mehdi, MSc * ; Mirnajafi-Zadeh Javad, PhD ** Received: 21/June /2008 Accepted: 28 /Feb /2009 Background: The use of low-frequency electrical stimulation () 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 on perforant path kindling acquisition. Materials and Methods: Sixty four male Wistar rats were stimulated by perforant path stimulation in a rapid kindling manner (6 stimulations per day). The (1 Hz) was applied immediately after termination of each kindling stimulation. The (1µM; i.c.v.), a serine/threonine protein phosphatase inhibitor and okadaic acid (1µM;i.c.v.), a serine/threonine protein phosphatases 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 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. Results: Appling immediately after kindling stimulation significantly retarded the kindling acquisition and delayed the expression of different kindled seizure stages. In addition, significantly reduced the increment of daily after-discharge duration during kindling development. Microinjection of neither nor okadaic acid had significant effect on the antiepileptogenic effect of on kindling parameters. Conclusion: Our findings showed that activation of and, which play a critical role in, induced down-regulation of synaptic strength, had no role in mediating the inhibitory effects of on perforant path kindled seizures. KEYWORDS: Seizure, Epilepsy, Low-frequency stimulation, Kindling *Instructor, Neuroscience Research Center, Kerman University of Medical Sciences and Health Services, Kerman, Iran and Dept of Physiology, Faculty of Medicine, Zabol University of Medical Sciences and Health Services, Zabol, Iran **Associate Prof, Neuroscience Research Center, Kerman University of Medical Sciences and Health Services, Kerman, Iran and Dept of Physiology, Faculty of Medicine, Tarbiat Modares University, Tehran, Iran

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