1. Children's Hospital, Shaanxi Provincial People's Hospital, Xi'an 710068, China.
2. Department of Orthopedics, Shaanxi Provincial People's Hospital, Xi'an 710068, China.
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2022 Dec 25;51(6):707-715. doi: 10.3724/zdxbyxb-2022-0183.
To investigate the underlying molecular mechanisms by which silence information regulator (SIRT) 2 and glutaminase (GLS) in the amygdala regulate social behaviors in autistic rats.
Rat models of autism were established by maternal sodium valproic acid (VPA) exposure in wild-type rats and -knockout ( ) rats. Glutamate (Glu) content, brain weight, and expression levels of SIRT2, GLS proteins and apoptosis-associated proteins in rat amygdala at different developmental stages were examined, and the social behaviors of VPA rats were assessed by a three-chamber test. Then, lentiviral overexpression or interference vectors of GLS were injected into the amygdala of VPA rats. Brain weight, Glu content and expression level of GLS protein were measured, and the social behaviors assessed.
Brain weight, amygdala Glu content and the levels of SIRT2, GLS protein and pro-apoptotic protein caspase-3 in the amygdala were increased in VPA rats, while the level of anti-apoptotic protein Bcl-2 was decreased (all <0.01). Compared with the wild-type rats, rats displayed decreased expression of SIRT2 and GLS proteins in the amygdala, reduced Glu content, and improved social dysfunction (all <0.01). Overexpression of GLS increased brain weight and Glu content, and aggravated social dysfunction in VPA rats (all <0.01). Knockdown of GLS decreased brain weight and Glu content, and improved social dysfunction in VPA rats (all <0.01).
The glutamate circulatory system in the amygdala of VPA induced autistic rats is abnormal. This is associated with the upregulation of SIRT2 expression and its induced increase of GLS production; knocking out gene or inhibiting the expression of GLS is helpful in maintaining the balanced glutamate cycle and in improving the social behavior disorder of rats.
探讨沉默信息调节因子 2（SIRT2）和谷氨酰胺酶（GLS）在杏仁核中调节自闭症大鼠社会行为的潜在分子机制。
采用母鼠丙戊酸钠（VPA）暴露建立野生型和 SIRT2 基因敲除（ ）大鼠自闭症模型。检测不同发育阶段大鼠杏仁核中谷氨酸（Glu）含量、脑重及 SIRT2、GLS 蛋白表达水平，并通过三箱测试评估 VPA 大鼠的社会行为。然后，将 GLS 的慢病毒过表达或干扰载体注射到 VPA 大鼠的杏仁核中。测量脑重、杏仁核 Glu 含量和 GLS 蛋白表达水平，并评估社会行为。
VPA 大鼠脑重、杏仁核 Glu 含量及 SIRT2、GLS 蛋白和促凋亡蛋白 caspase-3 水平升高，而抗凋亡蛋白 Bcl-2 水平降低（均<0.01）。与野生型大鼠相比， 大鼠杏仁核 SIRT2 和 GLS 蛋白表达降低，Glu 含量减少，社会功能障碍改善（均<0.01）。GLS 过表达增加了 VPA 大鼠的脑重和 Glu 含量，加重了社会功能障碍（均<0.01）。GLS 敲低降低了 VPA 大鼠的脑重和 Glu 含量，改善了社会功能障碍（均<0.01）。
VPA 诱导自闭症大鼠杏仁核谷氨酸循环系统异常，这与 SIRT2 表达上调及其诱导的 GLS 产生增加有关；敲除 基因或抑制 GLS 的表达有助于维持平衡的谷氨酸循环，改善大鼠的社会行为障碍。
