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KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice

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Abstract

Autism spectrum disorders (ASD) are highly heterogeneous neurodevelopmental disorders characterized by impaired social interaction skills. Whole exome sequencing has identified loss-of-function mutations in lysine methyltransferase 2E (KMT2E, also named MLL5) in ASD patients and it is listed as an ASD high-risk gene in humans. However, experimental evidence of KMT2E in association with ASD-like manifestations or neuronal function is still missing. Relying on KMT2E+/− mice, through animal behavior analyses, positron emission tomography (PET) imaging, and neuronal morphological analyses, we explored the role of KMT2E haploinsufficiency in ASD-like symptoms. Behavioral results revealed that KMT2E haploinsufficiency was sufficient to produce social deficit, accompanied by anxiety in mice. Whole-brain 18F-FDG-PET analysis identified that relative amygdala glycometabolism was selectively decreased in KMT2E+/− mice compared to wild-type mice. The numbers and soma sizes of amygdala neurons in KMT2E+/− mice were prominently increased. Additionally, KMT2E mRNA levels in human amygdala were significantly decreased after birth during brain development. Our findings support a causative role of KMT2E in ASD development and suggest that amygdala neuronal development abnormality is likely a major underlying mechanism.

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All data generated, collected, and analyzed here are available from the corresponding author upon reasonable request.

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Funding

This work was supported financially by grants from National Natural Science Foundation of China (No. 81972362 and 82173197 to X.Q.C; 81801760 to C.-Y.L), and the Fundamental Research Funds for the Central Universities (HUST: 2019kfyXJJS081 to P.Z.).

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  1. Yuan-Jun Li, Chun-Yan Li, and Chun-Yang Li contributed equally to this work.

Authors and Affiliations

  1. Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430032, China

    Yuan-Jun Li, Chun-Yang Li, Dian-Xing Hu, Zhi-Bo Xv, Shu-Han Zhang & Xiao-Qian Chen

  2. Department of Nuclear Medicine, Hubei Province Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Chun-Yan Li & Xiao-Li Lan

  3. Translational Medical Center for Development and Disease, Institute of Pediatrics, Shanghai Key Laboratory of Birth Defect, Children’s Hospital of Fudan University, Shanghai, 201102, China

    Qiang Li

  4. Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430032, China

    Pei Zhang & Bo Tian

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  1. Yuan-Jun Li
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Contributions

Conceptualization, Y.-J.L., Q.L., and X.-Q.C.; methodology, Y.-J.L., C.L., C.-Y.L., D.-X.H., Q.L., X.L., and P.Z.; investigation, Y.-J.L., C.L., C.-Y.L., D.-X.H., Z.-B.X., and S.-H.Z.; manuscript writing, Y.-J.L., P.Z., and X.-Q.C.; funding acquisition, X.-Q.C.; resources, Q.L., X.L., P.Z., and X.-Q.C.; supervision, X.L., P.Z., and X.-Q.C.

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Correspondence to Xiao-Li Lan or Xiao-Qian Chen.

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Animal care, handling, and all experiments were performed according to the guidelines of the National Institutes of Health of the United States and approved by the ethics committee of Tongji Medical College of Huazhong University of Science and Technology.

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Li, YJ., Li, CY., Li, CY. et al. KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice. Mol Neurobiol 60, 1609–1625 (2023). https://doi.org/10.1007/s12035-022-03167-w

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