TY - JOUR
T1 - Inhibiting proBDNF to mature BDNF conversion leads to ASD-like phenotypes in vivo
AU - Yang, Feng
AU - You, He
AU - Mizui, Toshiyuki
AU - Ishikawa, Yasuyuki
AU - Takao, Keizo
AU - Miyakawa, Tsuyoshi
AU - Li, Xiaofei
AU - Bai, Ting
AU - Xia, Kun
AU - Zhang, Lingling
AU - Pang, Dizhou
AU - Xu, Yiran
AU - Zhu, Changlian
AU - Kojima, Masami
AU - Lu, Bai
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2024/11
Y1 - 2024/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85193421814&partnerID=8YFLogxK
U2 - 10.1038/s41380-024-02595-5
DO - 10.1038/s41380-024-02595-5
M3 - 学術論文
C2 - 38762692
AN - SCOPUS:85193421814
SN - 1359-4184
VL - 29
SP - 3462
EP - 3474
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 11
ER -
