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

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Abstract

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 in drosophila. 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 glial cells or neurons could induce epilepsy in drosophila. 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 make a precise treatment case by case.

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Data Availability

Raw data were generated at Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University. Derived data supporting the findings of this study are available from the corresponding author on request.

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Acknowledgements

RNAi fly lines were donated from Tsing-Hua Fly Stock Center.

Funding

This work was supported by Guangzhou Medical University (No. 2019A023) and Guangzhou Postdoc Startup Fund (Jing-Da Qiao).

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Authors and Affiliations

  1. Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

    Jin-Ming Zhang, Ya-Ping Li, Zi-Jing Ye & Jing-da Qiao

  2. The Third Medicine School, Guangzhou Medical University, Guangzhou, China

    Ming-Jie Chen & Jiong-Hui He

  3. The First Clinical Medicine School, Guangzhou Medical University, Guangzhou, China

    Zhi-Cai Li

  4. School of Pediatrics, Guangzhou Medical University, Guangzhou, China

    Yong-Hui Bao

  5. School of Public Health, Guangzhou Medical University, Guangzhou, China

    Bing-Jun Huang

  6. KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China

    Wen-Jie Zhang

  7. School of Veterinary Science, University of Sydney, Sydney, Australia

    Ping Kwan

  8. Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Yu-Ling Mao

  9. Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Yu-Ling Mao

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  1. Jin-Ming Zhang
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Contributions

Study design: JM Zhang and JD Qiao. Bioinformatic experiment: YP Li. Manuscript writing: JM Zhang, MJ Chen, JH He, P Kwan, YL Mao, and JD Qiao. Experiment performance and data analysis: JM Zhang, MJ Chen, JH He, ZC Li, YP Li, ZJ Ye, YH Bao, BJ Huang, WJ Zhang, YL Mao, and JD Qiao.

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Correspondence to Yu-Ling Mao or Jing-da Qiao.

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The original online version of this article was revised: The authors would like to add some more detail for the "Fly Stocks" information for the published article: Zhang et al., 2022, J. Mol. Neurosci. 72(8): 1706—1714.

In section "Methods and Materials", details of subsection "Fly Stocks" should be modified to "The flies were fed standard cornmeal and maintained in the incubator at 25 °C and 60–70% humidity on a 12:12-h light/dark cycle. UAS-Lrp1-RNAi (THU3999/FBgn0053087), UAS-Scn1a-RNAi (para-RNAi, positive control, THU1258/FBgn0264255), and UAS-Eaat1-RNAi (THU5473/FBgn0026439) flies were donated by Tsing Hua Fly Center (Tsinghua University, Beijing, China). The double balancer line and UAS-Eaat1 (8202) were purchased from Bloomington Fly Stock Center (Bloomington, IN, USA). The Gal4 driver line tub-Gal4, elav-Gal4, and repo-Gal4 were a gift from Prof. LIU JiYong (Guangzhou Medical University, Guangzhou, China), and the UAS-mCD8::GFP line was a gift from Prof. KE Ya (The Chinese University of Hong Kong, Hong Kong). Canton-S was used as the WT line in this study.

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Zhang, JM., Chen, MJ., He, JH. et al. Ketone Body Rescued Seizure Behavior of LRP1 Deficiency in Drosophila by Modulating Glutamate Transport. J Mol Neurosci 72, 1706–1714 (2022). https://doi.org/10.1007/s12031-022-02026-6

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