Subicular pyramidal neurons gate drug resistance in temporal lobe epilepsy

Objective Drug‐resistant epilepsy causes great clinical danger and still lacks effective treatments. Methods Here, we used multifaceted approaches combining electrophysiology, optogenetics, and chemogenetics in a classic phenytoin‐resistant epilepsy model to reveal the key target of subicular pyramidal neurons in phenytoin resistance. Results In vivo neural recording showed that the firing rate of pyramidal neurons in the subiculum, but not other hippocampal subregions, could not be inhibited by phenytoin in phenytoin‐resistant rats. Selective inhibition of subicular pyramidal neurons by optogenetics or chemogenetics reversed phenytoin resistance, whereas selective activation of subicular pyramidal neurons induced phenytoin resistance. Moreover, long‐term low‐frequency stimulation at the subiculum, which is clinically feasible, significantly inhibited the subicular pyramidal neurons and reversed phenytoin resistance. Furthermore, in vitro electrophysiology revealed that off‐target use of phenytoin on sodium channels of subicular pyramidal neurons was involved in the phenytoin resistance, and clinical neuroimaging data suggested the volume of the subiculum in drug‐resistant patients was related to the usage of sodium channel inhibitors. Interpretation These results highlight that the subicular pyramidal neurons may be a key switch control of drug‐resistant epilepsy and represent a new potential target for precise treatments. ANN NEUROL 2019;86:626–640