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PTN activity in quiescent neural stem cells mediates Shank3 overexpression-induced manic behavior

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  • Hongwon Kim

    (Dongguk University
    The State University of New Jersey)

  • Byounggook Cho

    (Dongguk University)

  • Hyung Kyu Kim

    (Yonsei University College of Medicine)

  • Soi Kang

    (Dongguk University)

  • Saemin An

    (Dongguk University)

  • Daeyeol Kwon

    (Dongguk University)

  • Hee Young Kim

    (Yonsei University College of Medicine)

  • Jongpil Kim

    (Dongguk University)

Abstract

Mania is a complex psychiatric disease characterized by hyperactivity, elevated mood and reduced anxiety. Despite extensive studies on the mechanism of the manic episodes, the molecular targets that control manic pathogenesis remain largely unclear. Here, through single-cell RNA sequencing (scRNA-seq) analysis, we show aberrant adult neurogenesis due to increased numbers of quiescent neural stem cells (qNSC) in a manic mouse model with Shank3 overexpression. Particularly, we found that the excessive Pleiotrophin (PTN), released by dysregulated qNSCs, is a key factor contributing to the manic-like phenotypes in Shank3-overexpressing mouse models. Pharmacological and molecular inhibition of PTN in qNSCs rescued aberrant neurogenesis and effectively alleviated the manic-like social deficits observed in Shank3-overexpressing mice. Taken together, our findings present an approach for modulating PTN activity in qNSCs, proposing it as a promising therapeutic target for manic development.

Suggested Citation

  • Hongwon Kim & Byounggook Cho & Hyung Kyu Kim & Soi Kang & Saemin An & Daeyeol Kwon & Hee Young Kim & Jongpil Kim, 2025. "PTN activity in quiescent neural stem cells mediates Shank3 overexpression-induced manic behavior," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57699-5
    DOI: 10.1038/s41467-025-57699-5
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