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<p>Chronic neuroinflammation gives rise to diverse microglial states across the brain, yet how region-specific microglial remodeling contributes to cognitive dysfunction remains unclear. Here we report that synapse-engulfing microglia in the thalamus drive cognitive impairment after cortical brain damage in mice, primarily studied in females. Region-specific manipulations of microglia during the chronic phase show that reactive microglial changes in the thalamus, but not in the hippocampus, impair recognition memory. Single-cell RNA sequencing reveals an enrichment of synapse-engulfing CD9<sup>hi</sup> microglia in the thalamus. Antibody-based CD9 blockade in the thalamus, as well as microglia-selective CD9 disruption, rescues thalamic synaptic loss, restores neuronal activity, and improves recognition memory. Further analysis shows that the blood-brain barrier disruption and subsequent γ-immunoglobulin (IgG) extravasation facilitate the generation of CD9<sup>hi</sup> microglia in an Fcγ receptor III-dependent manner. These findings demonstrate that the induction of synapse-engulfing CD9<sup>hi</sup> microglia in the thalamus by IgG/FcγRIII signaling drives recognition memory deficits following cortical damage.</p>

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FcγR- and CD9-dependent synapse-engulfing microglia in the thalamus drive cognitive impairment following cortical brain damage in mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月9日

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  • Ken Matoba,
  • Takahiro Kochi,
  • Oluwaseun Fatoba,
  • Md Sorwer Alam Parvez,
  • Inssaf Berkiks,
  • Yassin R. Mreyoud,
  • Harrison Strong,
  • Jana H. Badrani,
  • Hency Patel,
  • Yoshiko Nagaoka-Kamata,
  • Masakazu Kamata,
  • Hiroshi Tsujioka,
  • Toshihide Yamashita,
  • David K. Crossman,
  • Minae Niwa,
  • Shin-ichi Kano

摘要

Chronic neuroinflammation gives rise to diverse microglial states across the brain, yet how region-specific microglial remodeling contributes to cognitive dysfunction remains unclear. Here we report that synapse-engulfing microglia in the thalamus drive cognitive impairment after cortical brain damage in mice, primarily studied in females. Region-specific manipulations of microglia during the chronic phase show that reactive microglial changes in the thalamus, but not in the hippocampus, impair recognition memory. Single-cell RNA sequencing reveals an enrichment of synapse-engulfing CD9hi microglia in the thalamus. Antibody-based CD9 blockade in the thalamus, as well as microglia-selective CD9 disruption, rescues thalamic synaptic loss, restores neuronal activity, and improves recognition memory. Further analysis shows that the blood-brain barrier disruption and subsequent γ-immunoglobulin (IgG) extravasation facilitate the generation of CD9hi microglia in an Fcγ receptor III-dependent manner. These findings demonstrate that the induction of synapse-engulfing CD9hi microglia in the thalamus by IgG/FcγRIII signaling drives recognition memory deficits following cortical damage.