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<p>Selective serotonin reuptake inhibitors (SSRIs) exhibit delayed therapeutic effects despite rapid serotonin elevation, suggesting their dependence on slow neuroplastic adaptations. Here, we demonstrate that antidepressant actions require cell type-specific translational regulation of the peptidergic signaling in the dentate gyrus (DG). Chronic, but not acute, treatment with an SSRI fluoxetine (FLX) selectively enhances translational activity in hilar mossy cells (MCs), with no detectable changes in neighboring granule cells (GCs). Combining Translating Ribosome Affinity Purification (TRAP) with RNA sequencing revealed distinct baseline translatomes between these two glutamatergic neurons and identified FLX-induced remodeling of peptidergic pathways in the DG. Crucially, we discovered MC-specific enrichment of the neuropeptide PACAP, which undergoes translation-dependent upregulation by chronic FLX treatment. This PACAP induction mediates neuroadaptive plasticity in PAC1 receptor-expressing GCs and drives behavioral responses prominently in female mice during prolonged FLX administration. Our findings establish cell type-specific translational reprogramming as a novel mechanistic framework for antidepressant action.</p>

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Translational reprogramming of dentate gyrus peptidergic circuitry gates antidepressant efficacy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月3日

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  • Seo-Jin Oh,
  • Jin-hyeok Jang,
  • Jean-Pierre Roussarie,
  • Gyeong-un Jang,
  • Min-seok Jeong,
  • Yeon Suk Jo,
  • Chang-Hoon Shin,
  • Hongsoo Choi,
  • Kwang Lee,
  • Jong Hyuk Yoon,
  • Yong-Seok Oh

摘要

Selective serotonin reuptake inhibitors (SSRIs) exhibit delayed therapeutic effects despite rapid serotonin elevation, suggesting their dependence on slow neuroplastic adaptations. Here, we demonstrate that antidepressant actions require cell type-specific translational regulation of the peptidergic signaling in the dentate gyrus (DG). Chronic, but not acute, treatment with an SSRI fluoxetine (FLX) selectively enhances translational activity in hilar mossy cells (MCs), with no detectable changes in neighboring granule cells (GCs). Combining Translating Ribosome Affinity Purification (TRAP) with RNA sequencing revealed distinct baseline translatomes between these two glutamatergic neurons and identified FLX-induced remodeling of peptidergic pathways in the DG. Crucially, we discovered MC-specific enrichment of the neuropeptide PACAP, which undergoes translation-dependent upregulation by chronic FLX treatment. This PACAP induction mediates neuroadaptive plasticity in PAC1 receptor-expressing GCs and drives behavioral responses prominently in female mice during prolonged FLX administration. Our findings establish cell type-specific translational reprogramming as a novel mechanistic framework for antidepressant action.