Epilepsy Treatment through Genetic Intervention of GABAergic Interneurons: Promises and Challenges

Intractable forms of recurrent seizures occur in approximately 30% of epileptic patients. Therefore, development of new antiseizure therapies is of special urgency. Improvement of inhibition in epileptic circuitries is currently believed to be a promising strategy for treating epilepsy. This is mainly due to the following observations. A deficit of GABAergic transmission has been documented in epileptic patients and various animal models of epilepsy, and a pharmacological increase of synaptic GABA produces an anticonvulsive effect. Genetic intervention of GABAergic interneurons offers an opportunity to selectively modulate their activity. In recent years, the efficiency of on-demand control of seizures via opto- or chemogenetic modulation of inhibitory networks has been confirmed in various in vivo and acute brain slice models of epilepsy. It was found that suppression of seizures can be achieved by opto- or chemogenetic modulation of local and distant inhibitory neurons, and recruitment of a mixed population of GABAergic interneurons results in more potent seizure suppression than recruitment of their single subclasses. The major advantage of this strategy is that the activity of neuronal networks outside the epileptic zone and during interseizure intervals remains intact, thus preserving normal brain function. However, the dual role of inhibitory networks in ictogenesis may compromise the future development of this approach. In this review, we focus on recent advances in developing therapies for epilepsy treatment by genetic intervention of GABAergic INs, caveats to consider when manipulating the function of GABAergic INs using genetic tools, and considerations to overcome these caveats.