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<p>Ubiquinol cytochrome c reductase core protein I (UQCRC1) is a crucial subunit of Complex III, essential for its assembly. Reduced UQCRC1 expression impairs memory and spatial learning in mice, though the mechanisms are unclear. This study found that diminished UQCRC1 expression resulted in significant impairments in hippocampus-dependent cognition, which correlated with a notable decrease in UQCRC1 and synaptic proteins within the dentate gyrus (DG). RNA sequencing analysis of the hippocampus revealed a reduction in cilia, identified as a critical factor contributing to these cognitive deficits. Significantly, the overexpression of <i>Ttbk2</i> in the DG restored ciliary function and mitigated cognitive impairments. Additionally, <i>in vivo</i> electrophysiological experiments demonstrated that theta and gamma rhythms and wide-wave interneuron reactivity in the hippocampus DG were present in <i>Uqcrc1</i><sup>+/-</sup> mice and could be rescued through <i>Ttbk2</i> overexpression. These findings suggest that the downregulation of UQCRC1 expression contributes to cognitive decline by impairing neural oscillations and the functionality of wide-wave interneurons, likely due to ciliary damage.</p>

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Downregulation of UQCRC1 Expression Leads to Cognitive Decline by Disrupting the Cilia in the Dentate Gyrus

  • 期刊论文

  • 发表日期：

    2025年11月3日

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  • Jing Zhang,
  • Tianyao Liu,
  • Zonghong Long,
  • Zuoxi Wu,
  • Jing Luo,
  • Fuhai Bai,
  • Lianyu Zhou,
  • Hong Gong,
  • Meifeng Gong,
  • Hong Li,
  • Xiaotang Fan

摘要

Ubiquinol cytochrome c reductase core protein I (UQCRC1) is a crucial subunit of Complex III, essential for its assembly. Reduced UQCRC1 expression impairs memory and spatial learning in mice, though the mechanisms are unclear. This study found that diminished UQCRC1 expression resulted in significant impairments in hippocampus-dependent cognition, which correlated with a notable decrease in UQCRC1 and synaptic proteins within the dentate gyrus (DG). RNA sequencing analysis of the hippocampus revealed a reduction in cilia, identified as a critical factor contributing to these cognitive deficits. Significantly, the overexpression of Ttbk2 in the DG restored ciliary function and mitigated cognitive impairments. Additionally, in vivo electrophysiological experiments demonstrated that theta and gamma rhythms and wide-wave interneuron reactivity in the hippocampus DG were present in Uqcrc1+/- mice and could be rescued through Ttbk2 overexpression. These findings suggest that the downregulation of UQCRC1 expression contributes to cognitive decline by impairing neural oscillations and the functionality of wide-wave interneurons, likely due to ciliary damage.