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

Feng Yang; He You; Toshiyuki Mizui; Yasuyuki Ishikawa; Keizo Takao; Tsuyoshi Miyakawa; Xiaofei Li; Ting Bai; Kun Xia; Lingling Zhang; Dizhou Pang; Yiran Xu; Changlian Zhu; Masami Kojima; Bai Lu

doi:10.1038/s41380-024-02595-5

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

Mol Psychiatry. 2024 May 18. doi: 10.1038/s41380-024-02595-5. Online ahead of print.

Authors

Feng Yang^#^{1

2}, He You^#^{2

3}, Toshiyuki Mizui^#⁴, Yasuyuki Ishikawa⁵, Keizo Takao^{4

6

7}, Tsuyoshi Miyakawa^{4

8}, Xiaofei Li^{1

2}, Ting Bai⁹, Kun Xia⁹, Lingling Zhang¹⁰, Dizhou Pang¹¹, Yiran Xu¹⁰, Changlian Zhu¹⁰, Masami Kojima^{12

13}, Bai Lu^{14

15}

Affiliations

¹ China National Clinical Research Center for Neurological Diseases, Basic and Translational Medicine Center, Beijing Tiantan Hospital, Capital Medical University, 100070, Beijing, China.
² Advanced Innovation Center for Human Brain Protection, Capital Medical University, 100070, Beijing, China.
³ School of Pharmaceutical Sciences and IDG/McGovern Institute for Brain Research, Tsinghua University, 100084, Beijing, China.
⁴ Core Research for Evolutional Science and Technology (CREST), Kawaguchi, 332-0012, Japan.
⁵ Department of Systems Life Engineering, Maebashi Institute of Technology, Maebashi, 371-0816, Japan.
⁶ Life Science Research Center, University of Toyama, Toyama, 930-0194, Japan.
⁷ Department of Behavioral Physiology, Graduate School of Innovative Life Science, University of Toyama, Toyama, 930-0194, Japan.
⁸ Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan.
⁹ Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
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.
¹¹ Center for Child Behavioral Development, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
¹² Core Research for Evolutional Science and Technology (CREST), Kawaguchi, 332-0012, Japan. masamikojima@neptune.kanazawa-it.ac.jp.
¹³ Biomedical Department of Applied Bioscience, College of Bioscience and Chemistry, Kanazawa Institute of Technology (KIT), Ishikawa, 924-0838, Japan. masamikojima@neptune.kanazawa-it.ac.jp.
¹⁴ Advanced Innovation Center for Human Brain Protection, Capital Medical University, 100070, Beijing, China. bai_lu@mail.tsinghua.edu.cn.
¹⁵ School of Pharmaceutical Sciences and IDG/McGovern Institute for Brain Research, Tsinghua University, 100084, Beijing, China. bai_lu@mail.tsinghua.edu.cn.

^# Contributed equally.

PMID: 38762692
DOI: 10.1038/s41380-024-02595-5

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 (BDNF^met/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 BDNF^met/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.

Abstract

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