Effect of repeated transcranial magnetic stimulation during epileptogenesis on spontaneous activity of hippocampal CA1 pyramidal neurons in rats

Introduction: Considering the antiepileptogenic effects of repeated transcranial magnetic stimulation (rTMS), the effect of rTMS applied during amygdala kindling on spontaneous activity of hippocampal CA1 pyramidal neurons was investigated. Materials and Methods: A tripolar electrode was inserted in basolateral amygdala of Male Wistar rats. After a recovery period, animals received daily kindling stimulations until they reached stage 5 seizure. In one group of animals, rTMS at frequency of 1 Hz were applied to hippocampus once daily at 5 min after termination of kindling stimulations. 24 h after the last kindling stimulation, spontaneous activity of CA1 pyramidal neurons of the hippocampus was investigated using whole cell patch clamp technique. Results: Kindling-induced seizures resulted in increment of spontaneous activity of hippocampal CA1 neurons, but application of rTMS during amygdala kindling prevented it. Moreover, rTMS administration inhibited the kindling-induced enhancement of afterdepolarization (ADP) amplitude and action potential duration. Conclusion: Results of this study suggest that rTMS exerts its anticonvulsant effect, in part, through preventing the amygdala kindling-induced increase in spontaneous activity and excitability of hippocampal CA1 pyramidal neurons. Antiepileptogenic effect of rTMS in kindling Physiol Pharmacol 19 (2015) 113 | 2 (Devinsky, 1991). Surgical removal of epileptogenic tissue, particularly the hippocampus, often results in pharmacologically controlled seizures after surgery (Wiebe et al., 2001, Spencer, 2002, Spencer and Burchiel, 2012), implying that the hippocampus plays a crucial role in the drug-resistant temporal lobe epilepsy. The failure of current therapies in controlling the refractory epileptic seizures highlights the need for new, effective, and safe treatments. Transcranial magnetic stimulation (TMS) is a novel technique for noninvasive stimulation of brain through intact scalp (Barker et al., 1985). It is a widely used method in research of human brain physiology and a therapeutic tool for some drug-resistant neuropsychiatric disorders (Dayan et al., 2013). It has been postulated that low frequency repetitive TMS (rTMS; ≤2 Hz) decreases, while high frequency rTMS (≥5 Hz) increases the cortical excitability (Pascual-Leone et al., 1994, Chen et al., 1997, Tergau et al., 1997, Kim et al., 2004). Furthermore, low frequency rTMS has been shown to have diverse degrees of seizure control in both epileptic patients (Tergau et al., 1999, Menkes and Gruenthal, 2000, Theodore et al., 2002, Misawa et al., 2005, Fregni et al., 2006, Joo et al., 2007, Santiago-Rodriguez et al., 2008) and in laboratory animals (Ebert and Ziemann, 1999, Fleischmann et al., 1999, Rotenberg et al., 2008, Mongabadi et al., 2013). Focal epilepsies are particularly ideal for the application of rTMS due to a delimited zone of increased excitability (SantiagoRodriguez et al., 2008). Considering the ability of rTMS as a potential therapeutic manner for epileptic patients, it is necessary to explore neuronal effects associated with its anti-epileptic outcome. Understanding these effects will also be useful in determining the probable side effects following application of rTMS. It has been suggested that long-term depressionor depotentiation-like mechanisms may be responsible for rTMS effects (Chen et al., 1997, Hallett, 2000, Kobayashi and Pascual-Leone, 2003, Tokay et al., 2009, Dayan et al., 2013). Kindling is a widely studied animal model of temporal lobe epilepsy in which repetitive focal electrical stimulation of the brain induces progressive seizure activity culminates in tonic-clonic convulsion (Sutula, 1990). Our recent study showed that application of rTMS can prevent kindling-induced synaptic potentiation (Yadollahpour et al., 2014). It has been shown that synaptic potentiation is accompanied with changes in electrophysiological properties of neurons (Hallett et al., 1999, Wagner et al., 2009, Pell et al., 2011). These changes can be observed in areas involved in seizure generation or propagation of amygdala kindling, including the hippocampus. Previous studies showed that CA1 region of the hippocampus is among the most important areas involved in the propagation of amygdala kindlinginduced seizures (Dasheiff and McNamara, 1982, Mirnajafi-Zadeh et al., 2002). Regarding the inhibitory effect of rTMS on epileptogenesis and considering the important role of CA1 pyramidal neurons in spreading of the amygdala kindling-induced seizures, in the present study, we investigated whether application of rTMS during amygdala kindling procedure can prevent the kindlinginduced changes in electrophysiological properties of hippocampal CA1 pyramidal neurons during amygdala kindling. Materials and methods