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<p>Major Depressive Disorder (MDD) is a serious mental illness, and neuroinflammation is increasingly recognized as a contributor to its pathogenesis; however, the underlying cellular and molecular mechanisms remain largely unknown. In this study, we performed single-nucleus RNA sequencing to profile prefrontal cortex transcriptomics in interleukin-15 receptor subunit alpha knockout (<i>Il15ra</i><sup><i>-/-</i></sup>) mice displaying depressive-like behaviors. <i>Il15ra</i><sup><i>-/-</i></sup> mice exhibited cell-type-specific transcriptomic alterations, particularly affecting synapse assembly. Co-expression network analysis identified two gene clusters predominantly linked to synaptic pathways in microglia, excitatory neurons, and interneurons, suggesting dysregulated neuron-microglial interactions in depression. Morphological analysis revealed microglial activation and synapse remodeling driven by enhanced neuron-microglia communication via the CX3CL1/CX3CR1 signaling pathway. Pharmacological inhibition of CX3CL1/CX3CR1 signaling using a CX3CR1 antagonist reversed depressive-like behaviors and microglia-mediated excessive synapse pruning caused by IL-15RA deficiency. Collectively, these findings demonstrate that IL-15RA deficiency contributes to depression onset by modulating microglia-mediated synaptic remodeling, highlighting a targetable neuroimmune pathway for therapeutic interventions in MDD.</p>

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IL-15 receptor alpha deficiency triggers depressive-like behaviors via enhanced microglial synapse pruning

  • 期刊论文

  • 发表日期：

    2026年4月22日

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  • Yue Tang,
  • Yu Huang,
  • Jing Pan,
  • Chaolan Li,
  • Jie Yang,
  • Xunmin Tan,
  • Kangan Hu,
  • Lu Wen,
  • Peijun Xie,
  • Yuxiang Liu,
  • Haotian Xu,
  • Shixin Cao,
  • Jianping Zhang,
  • Yifan Li,
  • Ping Liu,
  • Minghao Yuan,
  • Xiaodong Song,
  • Jing Wu,
  • Yi He,
  • Ma-Li Wong,
  • Julio Licinio,
  • Peng Zheng

摘要

Major Depressive Disorder (MDD) is a serious mental illness, and neuroinflammation is increasingly recognized as a contributor to its pathogenesis; however, the underlying cellular and molecular mechanisms remain largely unknown. In this study, we performed single-nucleus RNA sequencing to profile prefrontal cortex transcriptomics in interleukin-15 receptor subunit alpha knockout (Il15ra-/-) mice displaying depressive-like behaviors. Il15ra-/- mice exhibited cell-type-specific transcriptomic alterations, particularly affecting synapse assembly. Co-expression network analysis identified two gene clusters predominantly linked to synaptic pathways in microglia, excitatory neurons, and interneurons, suggesting dysregulated neuron-microglial interactions in depression. Morphological analysis revealed microglial activation and synapse remodeling driven by enhanced neuron-microglia communication via the CX3CL1/CX3CR1 signaling pathway. Pharmacological inhibition of CX3CL1/CX3CR1 signaling using a CX3CR1 antagonist reversed depressive-like behaviors and microglia-mediated excessive synapse pruning caused by IL-15RA deficiency. Collectively, these findings demonstrate that IL-15RA deficiency contributes to depression onset by modulating microglia-mediated synaptic remodeling, highlighting a targetable neuroimmune pathway for therapeutic interventions in MDD.