Subicular pyramidal neurons gate drug resistance in temporal lobe epilepsy

Objective

Drug resistant epilepsy causes great danger in clinical 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, while 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. Further, in vitro electrophysiology revealed that off‐target of phenytoin on sodium channels of subicular pyramidal neurons were involved in the phenytoin resistance, and clinical neuroimage data suggested the volume of the subiculum in drug‐resistant patients was related with 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.

Abstract