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<p>Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive behaviors. Recent studies have&#xa0;indicated that heterozygous mutations in the mixed lineage leukemia 5 (<i>MLL5</i>) gene are implicated in ASD susceptibility and associated with neurodevelopmental abnormalities. However, the detailed mechanisms remain unclear. Here, we demonstrate that <i>Mll5</i> haploinsufficiency in mice impairs microglial phagocytosis, drives neuronal hyperexcitability, and recapitulates core ASD-like behaviors. We also show that <i>Mll5</i> acts as an epigenetic regulator, modulating microglial phagocytosis via the TREM2-SGK3-GSK3β signaling axis, which is associated with deficient glucose metabolism. Furthermore, microglia derived from individual with&#xa0;ASD exhibit parallel reductions in <i>MLL5</i> expression and phagocytic function. By targeting this pathway, lithium chloride, a GSK3β inhibitor, rescues both microglial phagocytosis deficits and behavioral abnormalities in <i>Mll5</i> haploinsufficienct mice. Our findings highlight <i>MLL5</i>’s critical role in ASD and its potential as a therapeutic target.</p>

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Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月17日

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  • Shumin Gao,
  • Qingxiu Lin,
  • Xiaotong Liu,
  • Meixiang Jia,
  • An-Yi Zhang,
  • Zhendong Feng,
  • Lei Han,
  • Nianzhuang Qiu,
  • Xiao-Xing Liu,
  • Huajie Zhai,
  • Haizhen Zhang,
  • Jing Zhang,
  • Xiaodan Ding,
  • Yan Zhang,
  • Lin Lu,
  • Jie Shi,
  • Jia Jia Liu,
  • Ya Bin Wei

摘要

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive behaviors. Recent studies have indicated that heterozygous mutations in the mixed lineage leukemia 5 (MLL5) gene are implicated in ASD susceptibility and associated with neurodevelopmental abnormalities. However, the detailed mechanisms remain unclear. Here, we demonstrate that Mll5 haploinsufficiency in mice impairs microglial phagocytosis, drives neuronal hyperexcitability, and recapitulates core ASD-like behaviors. We also show that Mll5 acts as an epigenetic regulator, modulating microglial phagocytosis via the TREM2-SGK3-GSK3β signaling axis, which is associated with deficient glucose metabolism. Furthermore, microglia derived from individual with ASD exhibit parallel reductions in MLL5 expression and phagocytic function. By targeting this pathway, lithium chloride, a GSK3β inhibitor, rescues both microglial phagocytosis deficits and behavioral abnormalities in Mll5 haploinsufficienct mice. Our findings highlight MLL5’s critical role in ASD and its potential as a therapeutic target.