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

研究成果: ジャーナルへの寄稿学術論文査読

抄録

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.

本文言語英語
ページ(範囲)3462-3474
ページ数13
ジャーナルMolecular Psychiatry
29
11
DOI
出版ステータス出版済み - 11-2024

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 細胞および分子神経科学
  • 精神医学および精神衛生

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