Schiller Y, Bankirer Y. Cellular mechanisms underlying antiepileptic effects of low-and high-frequency electrical stimulation in acute epilepsy in neocortical brain slices in vitro. J Neurophysiol 97: 1887J Neurophysiol 97: -1902J Neurophysiol 97: , 2007. First published December 6, 2006; doi:10.1152/jn.00514.2006. Approximately 30% of epilepsy patients suffer from drug-resistant epilepsy. Direct electrical stimulation of the epileptogenic zone is a potential new treatment modality for this devastating disease. In this study, we investigated the effect of two electrical stimulation paradigms, sustained low-frequency stimulation and short trains of high-frequency stimulation, on epileptiform discharges in neocortical brain slices treated with either bicuculline or magnesium-free extracellular solution. Sustained low-frequency stimulation (5-30 min of 0.1-to 5-Hz stimulation) prevented both interictal-like discharges and seizure-like events in an intensity-, frequency-, and distance-dependent manner. Short trains of high-frequency stimulation (1-5 s of 25-to 200-Hz stimulation) prematurely terminated seizure-like events in a frequency-, intensity-, and duration-dependent manner. Roughly one half the seizures terminated within the 100-Hz stimulation train (P Ͻ 0.01 compared with control), whereas the remaining seizures were significantly shortened by 53 Ϯ 21% (P Ͻ 0.01). Regarding the cellular mechanisms underlying the antiepileptic effects of electrical stimulation, both low-and high-frequency stimulation markedly depressed excitatory postsynaptic potentials (EPSPs). The EPSP amplitude decreased by 75 Ϯ 3% after 10-min, 1-Hz stimulation and by 86 Ϯ 6% after 1-s, 100-Hz stimulation. Moreover, partial pharmacological blockade of ionotropic glutamate receptors was sufficient to suppress epileptiform discharges and enhance the antiepileptic effects of stimulation. In conclusion, this study showed that both lowand high-frequency electrical stimulation possessed antiepileptic effects in the neocortex in vitro, established the parameters determining the antiepileptic efficacy of both stimulation paradigms, and suggested that the antiepileptic effects of stimulation were mediated mostly by short-term synaptic depression of excitatory neurotransmission.