Xu C, Wang Y, Zhang S, et al. - Since drug-resistant epilepsy results in great clinical danger and still lacks effective treatments, researchers intended to unveil the principal target of subicular pyramidal neurons in phenytoin resistance by using multifaceted approaches integrating electrophysiology, optogenetics, and chemogenetics in a classic phenytoin-resistant epilepsy model. They found that in phenytoin-resistant rats, phenytoin failed to inhibit the firing rate of pyramidal neurons in the subiculum, but not other hippocampal subregions. Reversal of phenytoin resistance was seen as a result of selective inhibition of subicular pyramidal neurons by optogenetics or chemogenetics, whereas phenytoin resistance was caused by selective activation of subicular pyramidal neurons. In drug-resistant patients, a link between the volume of the subiculum and usage of sodium channel inhibitors was demonstrated by clinical neuroimaging data. The possibility of subicular pyramidal neurons to be a key switch control of drug-resistant epilepsy was emphasized and these can be a novel potential target for precise treatments.