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<p>Integrin α3 is critical for proper neuron-glia cell adhesion and dendrite development, implicated in various neurodevelopmental disorders. In this study, mice deficient in integrin α3 (<i>NEX-Itga3</i><sup><i>-/-</i></sup> mice) exhibit behavioral anomalies that mirror Attention Deficit Hyperactivity Disorder (ADHD), including increased mobility, impulsive disinhibition and impaired working memory. The mutant mice exhibit a reduced hippocampal volume and decreased α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) surface distribution in the hippocampus. Utilizing two-pimaging combined with whole-cell recordings, diminished AMPAR function and increased prevalence of silent synapses were observed in the <i>NEX-Itga3</i><sup><i>-/-</i></sup> mice. Systemic treatment with methylphenidate (MPH) and intra-hippocampal administration of the dopamine D1 receptor agonist SKF81297 improved ADHD-like behaviors, associated with enhanced dopamine D1 receptor activity and increased insertion of AMPARs in the hippocampus. Our analysis of the ABCD database uncovered a significant positive correlation between reduced integrin α3 expression and the prevalence of ADHD in adolescent humans. By identifying hippocampal AMPAR regulation as a key pathway through which ITGA3 influences ADHD-related phenotypes, this study uncovers a previously underappreciated hippocampal mechanism in ADHD and suggests new therapeutic strategies targeting synaptic modulation and hippocampal circuits.</p><p></p>

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Downregulation of integrin α3 in ADHD mirrored in mutant mouse model by dopamine-dependent hippocampal AMPAR expression

  • 期刊论文

  • 发表日期：

    2025年12月15日

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  • Xiaojuan Yao,
  • Ruiying Chen,
  • Jingxiang Zhu,
  • Ruiqing Hou,
  • Shitong Xiang,
  • Tianye Jia,
  • Yuelin Gu,
  • Zhenyu Wang,
  • Han Hu,
  • Hongting Chen,
  • He Wang,
  • Jianfeng Feng,
  • Trevor W. Robbins,
  • Yingwei Wang,
  • Michael J. Higley,
  • Anthony J. Koleske,
  • Xiao Xiao

摘要

Integrin α3 is critical for proper neuron-glia cell adhesion and dendrite development, implicated in various neurodevelopmental disorders. In this study, mice deficient in integrin α3 (NEX-Itga3-/- mice) exhibit behavioral anomalies that mirror Attention Deficit Hyperactivity Disorder (ADHD), including increased mobility, impulsive disinhibition and impaired working memory. The mutant mice exhibit a reduced hippocampal volume and decreased α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) surface distribution in the hippocampus. Utilizing two-pimaging combined with whole-cell recordings, diminished AMPAR function and increased prevalence of silent synapses were observed in the NEX-Itga3-/- mice. Systemic treatment with methylphenidate (MPH) and intra-hippocampal administration of the dopamine D1 receptor agonist SKF81297 improved ADHD-like behaviors, associated with enhanced dopamine D1 receptor activity and increased insertion of AMPARs in the hippocampus. Our analysis of the ABCD database uncovered a significant positive correlation between reduced integrin α3 expression and the prevalence of ADHD in adolescent humans. By identifying hippocampal AMPAR regulation as a key pathway through which ITGA3 influences ADHD-related phenotypes, this study uncovers a previously underappreciated hippocampal mechanism in ADHD and suggests new therapeutic strategies targeting synaptic modulation and hippocampal circuits.