Ketone Body Rescued Seizure Behavior of LRP1 Deficiency by Modulating Glutamate Transport

LRP1, the low-density lipoprotein receptor 1, would be a novel candidate gene of Epilepsy according to our bioinformatic results and the animal study. In this study, we explored the role of LRP1 in Epilepsy and whether Beta-hydroxybutyrate, the principal ketone body of the ketogenic diet, can treat epilepsy caused by LRP1 deficiency. UAS/GAL4 system was used to establish different genotype models. Flies were given Standard, High-sucrose, and ketone body food randomly. The bang-sensitive test was performed on flies and seizure-like behavior was assessed. In morphologic experiments, we found that LRP1 deficiency caused partial loss of the ellipsoidal body and partial destruction of the fan-shaped body. Whole-body and glia LRP1 defect flies had a higher seizure rate compared to the control group. Ketone body decreased the seizure rate in behavior test in all LRP1 defect flies, compared to Standard and High sucrose diet. Overexpression of glutamate transporter gene Eaat1 could mimic the ketone body effect on LRP1 deficiency flies. This study demonstrated that LRP1 defect globally or in astrocytes or neurons could induce epilepsy. The ketone body efficaciously rescued epilepsy caused by LRP1 knockdown. The results support screening for LRP1 mutations as discriminating conduct for individuals who require clinical attention and further clarify the mechanism of the ketogenic diet in Epilepsy, which could help Epilepsy patients making a precise treatment case by case.