Optogenetic dissection of ictogenesis: in search of a targeted anti-epileptic therapy

For over a century, epileptic seizures have been characterized as a state of pathological, hypersynchronous brain activity. Anti-epileptic therapies have been developed largely based on the dogma that the altered brain rhythms result from an overabundance of glutamatergic activity or insufficient GABAergic inhibition. The most effective drugs in use today act to globally decrease excitation, increase inhibition, or decrease all activity. Unfortunately, such broad alterations to brain activity often lead to impactful side effects such as drowsiness, cognitive impairment, and sleep disruption. Recent advances in optical imaging, optogenetics, and chemogenetics have made it feasible to record and alter neuronal activity with single neuron resolution and genetically directed targeting. The goal of this review it to summarize the usage of these research tools in the study of ictogenesis (seizure generation) and propose a translational pathway by which these studies could result in novel clinical therapies. This manuscript is not intended to serve as an exhaustive list of optogenetic tools nor as a summary of all optogenetic manipulations in epilepsy research. Rather, we will focus on the tools and research aimed at dissecting the basic neuron-level interactions underlying ictogenesis.