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Inhibiting proBDNF to mature BDNF conversion leads to ASD-like phenotypes in vivo

Molecular Psychiatry (2024)Cite this article

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Abstract

Autism Spectrum Disorders (ASD) comprise a range of early age-onset neurodevelopment disorders with genetic heterogeneity. Most ASD related genes are involved in synaptic function, which is regulated by mature brain-derived neurotrophic factor (mBDNF) and its precursor proBDNF in a diametrically opposite manner: proBDNF inhibits while mBDNF potentiates synapses. Here we generated a knock-in mouse line (BDNFmet/leu) in which the conversion of proBDNF to mBDNF is attenuated. Biochemical experiments revealed residual mBDNF but excessive proBDNF in the brain. Similar to other ASD mouse models, the BDNFmet/leu mice showed reduced dendritic arborization, altered spines, and impaired synaptic transmission and plasticity in the hippocampus. They also exhibited ASD-like phenotypes, including stereotypical behaviors and deficits in social interaction. Moreover, the plasma proBDNF/mBDNF ratio was significantly increased in ASD patients compared to normal children in a case-control study. Thus, deficits in proBDNF to mBDNF conversion in the brain may contribute to ASD-like behaviors, and plasma proBDNF/mBDNF ratio may be a potential biomarker for ASD.

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Fig. 1: Decrease in brain volume and dendritic arborization in BDNFmet/leu mutants.
Fig. 2: Alterations in dendritic spines and interactions of postsynaptic proteins.
Fig. 3: Impairments in synaptic transmission and plasticity.
Fig. 4: ASD-like behavioral phenotypes.
Fig. 5: proBDNF and BDNF levels in human plasma.

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Data availability

The summary data of the BDNF mRNA expression in both ASD and healthy control postmortem brain samples are available from their respective original articles. RNA-seq data are sourced from human BrainEXP-NPD database, located at http://www.brainexpnpd.org/boxresult.html?value=BDNF=ASD.

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Acknowledgements

This work was supported by the Grant-in-Aid for Scientific Research on Priority Areas- Elucidation of neural network function in the brain-from the Ministry of Education, Culture, Sports, Science and Technology of Japan (22K06448) (M.K.), by JST, CREST (TM, HK, TH and MK JPMJCR0833), and by the National Natural Science Foundation of China (81861138013, 31730034, 81501105), funds from Beijing Advanced Innovation Center for Human Brain Protection, Beijing Academy of Artificial Intelligence (grant number 20222001736) to BL, and by the Beijing Natural Science Foundation (L222077 and IS23097) to FY. The funding organizations had no role in the study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Feng Yang, He You, Toshiyuki Mizui.

Authors and Affiliations

  1. China National Clinical Research Center for Neurological Diseases, Basic and Translational Medicine Center, Beijing Tiantan Hospital, Capital Medical University, 100070, Beijing, China

    Feng Yang & Xiaofei Li

  2. Advanced Innovation Center for Human Brain Protection, Capital Medical University, 100070, Beijing, China

    Feng Yang, He You, Xiaofei Li & Bai Lu

  3. School of Pharmaceutical Sciences and IDG/McGovern Institute for Brain Research, Tsinghua University, 100084, Beijing, China

    He You & Bai Lu

  4. Core Research for Evolutional Science and Technology (CREST), Kawaguchi, 332-0012, Japan

    Toshiyuki Mizui, Keizo Takao, Tsuyoshi Miyakawa & Masami Kojima

  5. Department of Systems Life Engineering, Maebashi Institute of Technology, Maebashi, 371-0816, Japan

    Yasuyuki Ishikawa

  6. Life Science Research Center, University of Toyama, Toyama, 930-0194, Japan

    Keizo Takao

  7. Department of Behavioral Physiology, Graduate School of Innovative Life Science, University of Toyama, Toyama, 930-0194, Japan

    Keizo Takao

  8. Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan

    Tsuyoshi Miyakawa

  9. Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China

    Ting Bai & Kun Xia

  10. Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Lingling Zhang, Yiran Xu & Changlian Zhu

  11. Center for Child Behavioral Development, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Dizhou Pang

  12. Biomedical Department of Applied Bioscience, College of Bioscience and Chemistry, Kanazawa Institute of Technology (KIT), Ishikawa, 924-0838, Japan

    Masami Kojima

Authors
  1. Feng Yang
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  2. He You
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  3. Toshiyuki Mizui
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  15. Bai Lu
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Contributions

MK and TM (CREST) performed the biochemical assays, analyzed the data; TM (CREST) and YI, performed the electrophysiological experiments and analyzed the data; KT, TM (Fujita Health University, CREST), and MK engaged in the behavioral analysis of mice; TM (CREST), and MK performed the analysis of neuronal morphology and its quantitative analysis; YX, CZ, TB and KX collected plasma samples of ASD patients; FY, YX, XL and HY conducted the ELISA assay; FY performed the data analysis; FY, HY, TM, KT, TM, MK, and BL wrote the paper; BL and MK conceived and supervised the project.

Corresponding authors

Correspondence to Masami Kojima or Bai Lu.

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Yang, F., You, H., Mizui, T. et al. Inhibiting proBDNF to mature BDNF conversion leads to ASD-like phenotypes in vivo. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02595-5

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  • DOI: https://doi.org/10.1038/s41380-024-02595-5

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