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Regulation of activity in neuronal circuits is poorly understood. Alterations in regulatory mechanisms may underlie the transition from interictal to ictal activity. Epileptogenesis is thought to arise from hyperexcitability in populations of neurons, resulting from alterations in connectivity and synaptic physiology. Recent studies suggest that excitability in local circuits of neurons also can be changed by short-term plasticity induced by repetitive stimulation and actions of neuromodulators. It is suggested that these factors could be elements underlying excitability changes that contribute to the periodic nature of seizures.