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Dysfunction of Trio GEF1 involves in excitatory/inhibitory imbalance and autism-like behaviors through regulation of interneuron migration

Molecular Psychiatry volume 26, pages 7621–7640 (2021)Cite this article

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Abstract

Autism spectrum disorders (ASDs) are a group of highly inheritable neurodevelopmental disorders. Functional mutations in TRIO, especially in the GEF1 domain, are strongly implicated in ASDs, whereas the underlying neurobiological pathogenesis and molecular mechanisms remain to be clarified. Here we characterize the abnormal morphology and behavior of embryonic migratory interneurons (INs) upon Trio deficiency or GEF1 mutation in mice, which are mediated by the Trio GEF1-Rac1 activation and involved in SDF1α/CXCR4 signaling. In addition, the migration deficits are specifically associated with altered neural microcircuit, decreased inhibitory neurotransmission, and autism-like behaviors, which are reminiscent of some features observed in patients with ASDs. Furthermore, restoring the excitatory/inhibitory (E/I) imbalance via activation of GABA signaling rescues autism-like deficits. Our findings demonstrate a critical role of Trio GEF1 mediated signaling in IN migration and E/I balance, which are related to autism-related behavioral phenotypes.

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Fig. 1: Disruption of Trio in inhibitory progenitors results in abnormal orientation and morphology of leading process in migratory cortical INs and autism-like behaviors.
Fig. 2: Different distribution pattern of various IN subtypes in the mPFC and hippocampus but not SSC between Triofl/fl and Triofl/fl;Dlx5/6-CIE mice.
Fig. 3: Altered microcircuits, excitatory/inhibitory imbalance and increased seizure susceptibility were observed in the postnatal Triofl/fl;Dlx5/6-CIE mice.
Fig. 4: Rac1 activation by the Trio GEF1 domain is involved in SDF1α-CXCR4 signaling-mediated IN migration.
Fig. 5: Trio K1431M mutant mice showed abnormal IN migration, E/I imbalance and autism-like behaviors due to GEF1 dysfunction.

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The data that support the finding of this study are available upon reasonable request from the corresponding author.

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Acknowledgements

This work was supported by grants from Key Realm R&D Program of Guangdong Province (2019B030335001), the National Key R&D Program of China (2016YFC1307000), and the National Natural Science Foundation of China (81730037, 81871077, 81971283, and 82071541). We are thankful to Prof. Xiang Yu for her valuable help in suggesting the experimental design.

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  1. These authors contributed equally: Xiaoxuan Sun, Lifang Wang

Authors and Affiliations

  1. Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China

    Xiaoxuan Sun, Lifang Wang, Chengwen Wei, Mengwen Sun, Qiongwei Li, Hu Meng, Weihua Yue, Dai Zhang & Jun Li

  2. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China

    Mengwen Sun

  3. PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China

    Weihua Yue

  4. Chinese Institute for Brain Research, Beijing, China

    Dai Zhang

  5. Institute for Brain Research and Rehabilitation (IBRR), Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, China

    Dai Zhang

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JL and DZ designed the research; JL, XS, LW, CW, MS, QL, and HM performed the research and analyzed the data; MS, CW, XS, WY, JL, and DZ wrote and refined the article.

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Sun, X., Wang, L., Wei, C. et al. Dysfunction of Trio GEF1 involves in excitatory/inhibitory imbalance and autism-like behaviors through regulation of interneuron migration. Mol Psychiatry 26, 7621–7640 (2021). https://doi.org/10.1038/s41380-021-01109-x

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