Modeling the Interictal Epileptic State for Therapeutic Development with Tetanus Toxin

Abstract

Focal forms of epilepsy can result from a wide range of insults and can vary from focal symptoms to generalized convulsions. Most drugs that have been developed for epilepsy focus on the prevention of seizures. On Electroencephalography (EEG), seizures are characterized by a repetitive buildup of epileptic waveforms that can spread across the brain. Brain regions that produce seizures generate far more frequent ‘interictal’ spikes seen between seizures, and in animal models, these spikes occur prior to the development of seizures. Interictal spiking by itself has been shown to have significant adverse clinical effects on cognition and behavior in both patients and animal models. While the exact relationships between interictal spiking and seizures are not well defined, interictal spikes serve as an important biomarker that, for some forms of epilepsy, can serve as a surrogate biomarker and as a druggable target. While there are many animal models of seizures for drug development, here we review models of interictal spiking, focusing on tetanus toxin, to study the relationship between interictal spiking, seizures, cognition, and behavior. Studies on human cortical regions with frequent interictal spiking have identified potential therapeutic targets; therefore, having a highly consistent model of spiking will be invaluable not only for unraveling the initial stages of the pathological cascade leading to seizure development but also for testing novel therapeutics. This review offers a succinct overview of the use of tetanus toxin animal models for studying and therapeutic development for interictal spiking.