BRAIN-WIDE LIGHT-SHEET IMAGING OF BEXICASERIN-INDUCED CIRCUIT MODULATION IN A DBA/1 MOUSE MODEL OF SUDDEN UNEXPECTED DEATH IN EPILEPSY (SUDEP)

Patients with epilepsy, particularly those with developmental and epileptic encephalopathies (DEEs), are at risk for sudden unexpected death in epilepsy (SUDEP). Bexicaserin (LP352), a potent and highly selective 5-HT2C receptor superagonist, is an investigational drug currently in development for the treatment of seizures in patients with DEEs. Here we utilized brain-wide imaging to measure c-Fos protein to characterize the brain circuits modulated by bexicaserin in the context of seizures and respiratory arrest in DBA/1 mice. Tone presentation to DBA/1 mice induced wild running, generalized tonic-clonic seizures, and respiratory arrest. Highly susceptible mice were orally administered vehicle or bexicaserin prior to testing. Following testing, whole brains were dissected and cleared for brain-wide immunolabeling of the immediate early gene (IEG) c-Fos using iDISCO analysis. A separate cohort of mice were subjected to a similar protocol except that the mice remained in the homecage (ie, no chamber/tone presentation) after treatment. A robust increase in whole-brain c-Fos levels—notably in regions involved in auditory processing, seizures, and respiratory control—was observed in vehicle-treated mice exposed to the tone stimulus compared with mice only exposed to the chamber, consistent with the expected behavioral phenotypes of seizures and respiratory arrest triggered by tone presentation. Remarkably, bexicaserin suppressed c-Fos expression in these regions for all mice treated, which corresponded with reductions in seizures and respiratory arrest. These effects of bexicaserin were not observed in basal conditions (ie, homecage environment), further suggesting that bexicaserin attenuates pathological brain activity linked to life-threatening epilepsy-associated conditions such as SUDEP.