Kim Hongwon, Cho Byounggook, Kim Hyung Kyu, Kang Soi, An Saemin, Kwon Daeyeol, Kim Hee Young, Kim Jongpil
Department of Chemistry, Dongguk University, Pildong-ro 1-gil 30, Jung-gu, Seoul, 04620, Republic of Korea.
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.
Nat Commun. 2025 Mar 11;16(1):2435. doi: 10.1038/s41467-025-57699-5.
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.
躁狂症是一种复杂的精神疾病，其特征为多动、情绪高涨和焦虑减轻。尽管对躁狂发作的机制进行了广泛研究，但控制躁狂发病机制的分子靶点仍在很大程度上不清楚。在这里，通过单细胞RNA测序（scRNA-seq）分析，我们发现在过度表达Shank3的躁狂小鼠模型中，由于静止神经干细胞（qNSC）数量增加，导致异常的成年神经发生。特别是，我们发现失调的qNSC释放的过多多效生长因子（PTN）是导致过度表达Shank3的小鼠模型出现躁狂样表型的关键因素。对qNSC中的PTN进行药理学和分子抑制可挽救异常的神经发生，并有效减轻在过度表达Shank3的小鼠中观察到的躁狂样社交缺陷。综上所述，我们的研究结果提出了一种调节qNSC中PTN活性的方法，表明它是躁狂症治疗的一个有前景的靶点。
