Synaptotagmin-7 deficit causes insulin hypoactivity and contributes to behavioral alterations in mice

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-04-04 DOI:10.1016/j.isci.2025.112354

Yao-Nan Liu , Qiu-Wen Wang , Si-Yao Lu , Wei Shen , Chongye Guo , Zhikai Xing , Chang Li , Shan Sun , Sen-Fang Sui , Shuangli Mi , Fred H. Gage , Jun Yao

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Abstract

Synaptotagmin-7 (Syt7) KO mice show diurnal fluctuations of mania- and depression-like behavioral abnormalities. Although GluN2B-NMDAR hypoactivity has been shown to be involved in the induction of mania-like behaviors of the Syt7 KO mice in the dark phase, the reasons for the depression-like behaviors in the light phase and behavioral fluctuation remain unknown. Here, we show that bipolar I disorder (BDI)-patient-induced pluripotent stem cell (iPSC)-derived islet-like organoids exhibited Syt7-dependent insulin secretion defects; moreover, Syt7-deficiency-induced insulin hyposecretion generated depression-like behaviors in Syt7 KO mice in the light phase. Furthermore, pancreatic insulin secretion and neuronal activity showed opposite diurnal patterns, in which the Syt7-deficiency-induced disequilibrium induced periodic antagonistic shifts in the mania- and depression-like behaviors. Finally, using RNA sequencing (RNA-seq) analysis, we explored downstream pathways that might underlie the diurnal fluctuation of behaviors. Therefore, Syt7-deficiency-induced insulin hypoactivity contributed to light-phase depression-like behaviors and diurnal behavioral fluctuations in the mice.

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synaptotagin -7缺陷导致小鼠胰岛素活性降低并导致行为改变

synaptotagin -7 (Syt7) KO小鼠表现出躁狂和抑郁样行为异常的日波动。虽然GluN2B-NMDAR低活性参与了Syt7 KO小鼠黑暗期躁狂样行为的诱导，但其光明期抑郁样行为和行为波动的原因尚不清楚。在这里，我们发现双相I型障碍（BDI）患者诱导的多能干细胞（iPSC）衍生的胰岛样器官表现出syt7依赖性胰岛素分泌缺陷；此外，Syt7缺乏引起的胰岛素分泌减少在Syt7 KO小鼠的光期产生抑郁样行为。此外，胰腺胰岛素分泌和神经元活动表现出相反的昼夜模式，其中syt7缺陷引起的不平衡导致躁狂和抑郁样行为的周期性拮抗转变。最后，利用RNA测序（RNA-seq）分析，我们探索了可能导致行为日波动的下游途径。因此，syt7缺乏引起的胰岛素活性降低有助于小鼠轻度抑郁样行为和昼夜行为波动。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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