Anticonvulsant dopamine type 2 receptor agonist activates inhibitory parvalbumin interneurons

Dopamine type 2 receptor (D2R) agonists have anticonvulsant effect, whereas D2R antagonists increase seizure risk, but the mechanism of this action has not been delineated. We tested whether D2R agonists activate parvalbumin (PV)-containing inhibitory interneurons to suppress seizures. We treated frontal lobe onset seizures with a D2R agonist sumanirole, and it suppressed seizures. We used activity reporter TRAP2 mice and found that injection of D2R agonist led to extensive activation of PV interneurons in the cortex and striatum ipsilateral to the seizure focus. D2R agonists activate PV interneurons, which in turn inhibit principal neurons, potentially explaining their anticonvulsant effect.