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<p>Kabuki syndrome type 1 is a congenital multisystem disorder caused by <i>KMT2D</i> mutations. While some studies suggest that <i>KMT2D</i> deficiency may lead to autistic-like behaviors, the role of <i>KMT2D</i> in social behavior remains unconfirmed due to a lack of animal model evidence. In this study, we developed a mouse knockdown model and a zebrafish knockout model to investigate the role of <i>KMT2D</i> in synaptic function and behavioral patterns. We also performed an RNA sequencing analysis to delve into the molecular and cellular mechanisms of <i>KMT2D</i>. Results showed that <i>Kmt2d</i> deficiency in mouse and zebrafish both exhibited autistic-like behaviors including social behaviors defects and repetitive behavior. Additionally, knockdown of <i>Kmt2d</i> in the mouse hippocampus decreases excitatory and increases inhibitory synaptic transmission, disrupting the excitation-inhibition balance—a hallmark of autistic-like behaviors. RNA sequencing analysis revealed that under conditions of low <i>kmt2d</i> expression, differentially expressed genes were associated with glutamatergic and GABAergic synapses, supporting the dysregulation of excitation-inhibition balance in the hippocampus. Taken together, our research elucidates the critical role of KMT2D in modulating animal social behavior, potentially through its impact on synaptic excitation-inhibition balance.</p>

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Deficiency of KMT2D causes autistic-like behavior in mice and zebrafish

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月29日

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  • Huakun Shangguan,
  • Jingguo Huang,
  • Xia Wei,
  • Jie Huang,
  • Zaicheng Cao,
  • Xingjingyan Chen,
  • Jiahui Yuan,
  • Jingrun Zhang,
  • Binbin Ye,
  • Ruofei Yan,
  • Ruimin Chen,
  • Wucheng Tao

摘要

Kabuki syndrome type 1 is a congenital multisystem disorder caused by KMT2D mutations. While some studies suggest that KMT2D deficiency may lead to autistic-like behaviors, the role of KMT2D in social behavior remains unconfirmed due to a lack of animal model evidence. In this study, we developed a mouse knockdown model and a zebrafish knockout model to investigate the role of KMT2D in synaptic function and behavioral patterns. We also performed an RNA sequencing analysis to delve into the molecular and cellular mechanisms of KMT2D. Results showed that Kmt2d deficiency in mouse and zebrafish both exhibited autistic-like behaviors including social behaviors defects and repetitive behavior. Additionally, knockdown of Kmt2d in the mouse hippocampus decreases excitatory and increases inhibitory synaptic transmission, disrupting the excitation-inhibition balance—a hallmark of autistic-like behaviors. RNA sequencing analysis revealed that under conditions of low kmt2d expression, differentially expressed genes were associated with glutamatergic and GABAergic synapses, supporting the dysregulation of excitation-inhibition balance in the hippocampus. Taken together, our research elucidates the critical role of KMT2D in modulating animal social behavior, potentially through its impact on synaptic excitation-inhibition balance.