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<p>Transcranial focused ultrasound (tFUS) enables non-invasive neuromodulation, yet its underlying molecular mechanisms remain largely elusive. Here, we show that transient receptor potential canonical 4 (TRPC4) and transient receptor potential canonical 5 (TRPC5) channels are critical mediators of tFUS-induced neuronal modulation in the mouse brain. Applying tFUS to the retrosplenial cortex (RSC) in male mice desensitizes mechanical and thermal sensitivity while robustly elicits early growth response 1 (Egr1) expression. Inhibiting these tFUS-induced Egr1 ensembles blocks the somatic sensory effects. Transcriptomic analysis identifies <i>Trpc4</i> enrichment in tFUS-activated Egr1-positive cells. Both pharmacological inhibition and genetic knockdown of TRPC4 abolish tFUS-mediated sensory modulation. Targeted knockdown further demonstrates that the highly homologous TRPC5 plays a comparable role. In situ proximity ligation assay, co-immunoprecipitation, and live-cell calcium imaging confirm that TRPC4 and TRPC5 form a protein complex in the RSC that facilitates the tFUS response. These findings establish TRPC4/TRPC5 as essential molecular components for tFUS neuromodulation.</p>

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TRPC4/TRPC5 are critical for neuronal modulation by transcranial focused ultrasound in retrosplenial cortex in male mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Cheng Wu,
  • Jie You,
  • Tao Sheng,
  • Guo-Feng Li,
  • Can Zhang,
  • Li Liu,
  • Li-Zhen Xu,
  • Wei Xiong,
  • Fan Yang,
  • Wei Yang,
  • Wei-Bao Qiu,
  • Hai-Rong Zheng,
  • Xiang-Yao Li

摘要

Transcranial focused ultrasound (tFUS) enables non-invasive neuromodulation, yet its underlying molecular mechanisms remain largely elusive. Here, we show that transient receptor potential canonical 4 (TRPC4) and transient receptor potential canonical 5 (TRPC5) channels are critical mediators of tFUS-induced neuronal modulation in the mouse brain. Applying tFUS to the retrosplenial cortex (RSC) in male mice desensitizes mechanical and thermal sensitivity while robustly elicits early growth response 1 (Egr1) expression. Inhibiting these tFUS-induced Egr1 ensembles blocks the somatic sensory effects. Transcriptomic analysis identifies Trpc4 enrichment in tFUS-activated Egr1-positive cells. Both pharmacological inhibition and genetic knockdown of TRPC4 abolish tFUS-mediated sensory modulation. Targeted knockdown further demonstrates that the highly homologous TRPC5 plays a comparable role. In situ proximity ligation assay, co-immunoprecipitation, and live-cell calcium imaging confirm that TRPC4 and TRPC5 form a protein complex in the RSC that facilitates the tFUS response. These findings establish TRPC4/TRPC5 as essential molecular components for tFUS neuromodulation.