Synergistic positive feedback underlying seizure initiation

Seizure onset is a critically important brain state transition that has proved very difficult to predict accurately from recordings of brain activity. Here we show that an intermittent optogenetic stimulation paradigm reveals a latent change in dendritic excitability that is tightly correlated to the onset of seizure activity. Our data show how the precipitous nature of the transition can be understood in terms of multiple, synergistic positive feedback mechanisms: raised intracellular Cl- and extracellular K+, coupled to a reduced threshold for dendritic plateau potentials, and which in turn leads to a switch to pyramidal burst firing. Notably, the stimulation paradigm also delays the evolving epileptic activity, meaning that not only can one monitor seizure risk safely, but it may also even have an additional anti-epileptic benefit.