LAUSR

Drug resistance is one of the most serious issues in epilepsy. Despite using various appropriate anti-epileptic drugs (AEDs), 30% of epilepsy patients are still drugresistant. The percentage of resistance in temporal lobe epilepsy (TLE) is even higher [1]. Although epilepsy surgery and deep brain stimulation are emerging as alternative therapeutic strategies, the curative outcome is still unsatisfactory. So far, the precise mechanisms of drug resistance are still ‘‘tales from the mist’’, which restricts the discovery of optimal targets and the further application of precise treatment. A recent study by Xu et al. [2] first revealed the critical ‘‘gating’’ role of subicular pyramidal neurons in drug-resistant TLE and unveiled the genesis of drug resistance in TLE at the neuronal level. At present, two major hypotheses of drug resistance in epilepsy have been put forward, although there is ongoing debate [3]: (1) the ‘‘drug-transporter hypothesis’’, in which AEDs are removed from epileptogenic tissue through the overexpression of multidrug transporters such as P-glycoprotein and multidrug resistance-associated proteins; and (2) the ‘‘target hypothesis’’, in which drug-target sensitivity declines in epileptogenic brain regions. In this report, Xu et al. first established a classic phenytoin (PHT)-resistant TLE model in male and female Wistar and SpragueDawley rats and found that increasing the concentration of PHT in the brain had no therapeutic effects on PHTresistant rats, which suggested that the drug-transporter hypothesis does not explain drug resistance. Thus, the authors focused on the target hypothesis. By in vivo neural recording, they showed for the first time that PHT loses its intrinsic inhibitory effect on the firing rate of subicular pyramidal neurons in PHT-resistant rats. This ‘‘off-target’’ phenomenon is site-specific, and is only evident in the subiculum but not in CA1, CA3, dentate gyrus, or entorhinal cortex. These results suggest that the ‘‘off-target’’ effect of PHT specifically in subicular pyramidal neurons is closely involved in PHT resistance. To explore the causality between the ‘‘off-target’’ effect and PHT resistance, they further used optogenetics and chemogenetics to precisely modulate subicular pyramidal neurons. The results showed that the resistance is reversed by selective inhibition of the subicular pyramidal neurons in PHT-resistant rats; while in PHT-responsive rats, the resistance is directly induced by the selective activation of these neurons. More interestingly, in a variety group (randomly PHT-responsive or non-responsive in three PHT screens), rats can be bi-directionally manipulated into becoming PHT-responsive or non-responsive by inhibiting or activating the subicular pyramidal neurons. However, the selective modulation of CA1 pyramidal neurons has no effect on PHT resistance. Therefore, the results provide the first direct in vivo evidence that subicular pyramidal neurons are sufficient and necessary for PHT resistance (Fig. 1), which provides a potential therapeutic target for drug-resistant epilepsy. Certainly, patients with drug-resistant TLE often exhibit a tendency for multidrug resistance. However, only PHT was tested in this report, so it would be valuable to further determine whether other AEDs similarly lack an inhibitory effect on subicular pyramidal neurons. & Kai Zhong [email protected]