Interneuron synchrony and the transition to spontaneous seizures

Epilepsy is one of the most pervasive neurological disorders, affecting 1% of the world's population, yet as many as 30% of patients are not helped by existing pharmacotherapies. In large part, this is due to a poor understanding of the mechanisms that cause an epileptic brain to spontaneously generate a seizure. With a better understanding of this process, seizure prevention therapies can be made more effective. The traditional theory of seizure generation proposed a breakdown of inhibitory processes, coupled with a build-up of excessive or "runaway" excitation. Conversely, recent studies observed that inhibitory interneurons are active at the earliest stage of seizure-like activity induced by a chemical or electrical stimulus. However, the role of interneurons in transitioning the brain to a seizure state when seizures occur spontaneously is unknown. We addressed this information gap by recording multiple single neurons and field potentials from the hippocampus of rats exhibiting chronic spontaneous seizures. Since seizures are characterized by synchronous neuronal activity, we first developed a method for estimating the degree to which neurons are coherent with local field oscillations. This and other measures were used to identify distinct patterns of interneuron synchrony before and during seizure, suggesting that the transition to seizure is not simply mediated by increasing global excitation. These patterns of activity were additionally used to inform an algorithm, which was able to predict seizures tens of seconds before ictal spiking began. This work offers the first detailed examination of the role of interneurons in the spontaneous transition to seizure, and demonstrates that this information not only advances our understanding of seizure generation, but could also be used practically to improve current therapeutic strategies.