An Electric Light Orchestra in the Brain: Optogenetics for Controlling Seizures via Modulation of Astrocyte Activity

Activated Astrocytes Attenuate Neocortical Seizures in Rodent Models Through Driving Na(+)-K(+)-ATPase Zhao J, Sun J, Zheng Y, Zheng Y, Shao Y, Li Y, Fei F, Xu C, Liu X, Wang S, Ruan Y, Liu J, Duan S, Chen Z, Wang Y. Nat Commun. 2022;13(1):7136. doi:10.1038/s41467-022-34662-2 Epileptic seizures are widely regarded to occur as a result of the excitation-inhibition imbalance from a neuro-centric view. Although astrocyte-neuron interactions are increasingly recognized in seizure, elementary questions about the causal role of astrocytes in seizure remain unanswered. Here we show that optogenetic activation of channelrhodopsin-2-expressing astrocytes effectively attenuates neocortical seizures in rodent models. This anti-seizure effect is independent from classical calcium signaling, and instead related to astrocytic Na+-K+-ATPase-mediated buffering K+, which activity-dependently inhibits firing in highly active pyramidal neurons during seizure. Compared with inhibition of pyramidal neurons, astrocyte stimulation exhibits anti-seizure effects with several advantages, including a wider therapeutic window, large-space efficacy, and minimal side effects. Finally, optogenetic-driven astrocytic Na+-K+-ATPase shows promising therapeutic effects in a chronic focal cortical dysplasia epilepsy model. Together, we uncover a promising anti-seizure strategy with optogenetic control of astrocytic Na+-K+-ATPase activity, providing alternative ideas and a potential target for the treatment of intractable epilepsy.