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Cerebellar dysfunction and schizophrenia-like behavior in Ebp1-deficient mice

Molecular Psychiatry volume 27, pages 2030–2041 (2022)Cite this article

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Abstract

Cerebellar deficits with Purkinje cell (PCs) loss are observed in several neurologic disorders. However, the underlying mechanisms as to how the cerebellum is affected during development remain unclear. Here we demonstrated that specific inactivation of murine Ebp1 in the central nervous system causes a profound neuropathology characterized by reduced cerebellar volume and PCs loss with abnormal dendritic development, leading to phenotypes including motor defects and schizophrenia (SZ)-like behaviors. Loss of Ebp1 leads to untimely gene expression of Fbxw7, an E3 ubiquitin ligase, resulting in aberrant protein degradation of PTF1A, thereby eliciting cerebellar defects. Reinstatement of Ebp1, but not the Ebp1-E183Ter mutant found in SZ patients, reconstituted cerebellar architecture with increased PCs numbers and improved behavioral phenotypes. Thus, our findings indicate a crucial role for EBP1 in cerebellar development, and define a molecular basis for the cerebellar contribution to neurologic disorders such as SZ.

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Fig. 1: Loss of Ebp1 in the mouse brain leads to cerebellar hypoplasia and motor defects.
Fig. 2: Ebp1-CKO mice display impaired PC development with altered dendritic morphology, but restoring Ebp1 rescues cerebellar defects.
Fig. 3: EBP1 regulates cerebellar transcription factor PTF1A stability through ubiquitin ligase FBXW7.
Fig. 4: EBP1 represses Fbxw7 transcription and leads to the function of PTF1A in PC development.
Fig. 5: SZ patient mutations in Ebp1 affect EBP1 function, but they are unable to rescue the cerebellar defects in CKO mutants.

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Acknowledgements

We are thankful to the Institute for Basic Science (IBS), Center for Neuroscience Imaging Research (IBS-R015-D1-2016-a00) for providing access to animal scanner and professional, technical support. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government [Ministry of Science, Information and Communication Technology and Future Planning (MSIP)] (2016R1A5A2945889 and 2020R1A2C2003268).

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Authors and Affiliations

  1. Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea

    Inwoo Hwang, Byeong-Seong Kim, Hyo Rim Ko, Seongbong Cho, Dongryeol Ryu & Jee-Yin Ahn

  2. Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea

    Inwoo Hwang, Byeong-Seong Kim & Jee-Yin Ahn

  3. Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Ho Yun Lee

  4. Department of Biochemistry and Molecular Biology, University of Ulsan, College of Medicine, Seoul, 05505, South Korea

    Sung-Woo Cho

  5. Department of Biochemistry, Chungbuk National University, Cheongju, South Korea

    Sungbo Shim

  6. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, 06351, South Korea

    Jee-Yin Ahn

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Contributions

Designed and analyzed the study, IH and J-YA; Performed Experiments, IH, B-SK, H-RK, SC, and SS; Performed MRI, IH, and H-YL; Analyzed Results, IH, S-WC, DR, and J-YA; Wrote Manuscript, J-YA.

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Correspondence to Jee-Yin Ahn.

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Hwang, I., Kim, BS., Ko, H.R. et al. Cerebellar dysfunction and schizophrenia-like behavior in Ebp1-deficient mice. Mol Psychiatry 27, 2030–2041 (2022). https://doi.org/10.1038/s41380-022-01458-1

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