恢复 IRSp53 缺失小鼠的社交障碍:对腹侧齿状回 Emx1 表达细胞的化学抑制。

IF 5.8 1区 医学 Q1 PSYCHIATRY Translational Psychiatry Pub Date : 2024-10-07 DOI:10.1038/s41398-024-03104-6
Su Hyun Kim, Bomee Lee, Seong Mi Lee, Yangsik Kim
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引用次数: 0

摘要

据报道,IRSp53 是一种突触支架蛋白,与精神分裂症、自闭症谱系障碍和基因敲除小鼠的社交障碍有关。识别与IRSp53缺失相关的关键脑区和细胞有望对精神疾病的治疗大有帮助。在这项研究中,我们对表达Emx1细胞(Emx1-Cre;IRSp53 flox/flox)的IRSp53缺失小鼠腹侧齿状回(vDG)进行了化学抑制。我们观察到,在Emx1-Cre;IRSp53 flox/flox小鼠的vDG内进行化学抑制后,社交障碍得到了恢复。此外,化学遗传激活也诱发了Emx1-Cre小鼠的社交障碍。CRHR1在Emx1-Cre;IRSp53 floatx/flox小鼠海马中的表达增加,CRHR1在化学基因抑制下减少。与对照组小鼠相比,Emx1-Cre;IRSp53 flox/flox小鼠海马的大体RNA测序结果显示Htd2、Ccn1和Atp61l减少,单细胞RNA测序结果显示Eya1和Ecrg4减少。这项研究确定,vDG是IRSp53缺失导致社交障碍的关键脑区。Emx1-Cre;IRSp53缺失/flox小鼠的社交障碍可通过化学抑制恢复,这为伴有社交障碍的精神疾病的新治疗方法提供了线索。
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Restoring social deficits in IRSp53-deleted mice: chemogenetic inhibition of ventral dentate gyrus Emx1-expressing cells.

IRSp53 is a synaptic scaffold protein reported to be involved in schizophrenia, autism spectrum disorders, and social deficits in knockout mice. Identifying critical brain regions and cells related to IRSp53 deletion is expected to be of great help in the treatment of psychiatric problems. In this study, we performed chemogenetic inhibition within the ventral dentate gyrus (vDG) of mice with IRSp53 deletion in Emx1-expressing cells (Emx1-Cre;IRSp53 flox/flox). We observed the recovery of social deficits after chemogenetic inhibition within vDG of Emx1-Cre;IRSp53 flox/flox mice. Additionally, chemogenetic activation induced social deficits in Emx1-Cre mice. CRHR1 expression increased in the hippocampus of Emx1-Cre;IRSp53 flox/flox mice, and CRHR1 was reduced by chemogenetic inhibition. Htd2, Ccn1, and Atp61l were decreased in bulk RNA sequencing, and Eya1 and Ecrg4 were decreased in single-cell RNA sequencing of the hippocampus in Emx1-Cre;IRSp53 flox/flox mice compared to control mice. This study determined that the vDG is a critical brain region for social deficits caused by IRSp53 deletion. Social deficits in Emx1-Cre;IRSp53 flox/flox mice were recovered through chemogenetic inhibition, providing clues for new treatment methods for psychiatric disorders accompanied by social deficits.

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来源期刊
CiteScore
11.50
自引率
2.90%
发文量
484
审稿时长
23 weeks
期刊介绍: Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.
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