抑制杏仁核沉默信息调节因子2和谷氨酰胺酶表达可改善自闭症大鼠社交行为  

Inhibiting silence information regulator 2 and glutaminase in the amygdala can improve social behavior in autistic rats

作　　者：张晓侠[1] 刘时璋[2] 刘晓梅[3] 王洁英[1] ZHANG Xiaoxia;LIU Shizhang;LIU Xiaomei;WANG Jieying(Children’s Hospital,Shaanxi Provincial People’s Hospital,Xi’an 710068,China;Department of Orthopedics,Shaanxi Provincial People’s Hospital,Xi’an 710068,China;Nursing Department,Shaanxi Provincial People’s Hospital,Xi’an 710068,China)

机构地区：[1]陕西省人民医院儿童病院,陕西西安710068 [2]陕西省人民医院骨科,陕西西安710068 [3]陕西省人民医院护理部,陕西西安710068

出　　处：《浙江大学学报（医学版）》2022年第6期707-715,共9页Journal of Zhejiang University(Medical Sciences)

基　　金：陕西省自然科学基础研究计划(2020JM-668)。

摘　　要：目的:探讨杏仁核中沉默信息调节因子(SIRT)2和谷氨酰胺酶(GLS)调节自闭症大鼠社交行为的潜在分子机制。方法:通过子宫丙戊酸钠暴露建立野生型和SIRT2基因敲除(SIRT2^(–/–))的自闭症大鼠模型,检测不同发育阶段大鼠脑质量,杏仁核中谷氨酸含量及SIRT2、GLS和凋亡相关蛋白的表达水平,并通过三箱社交行为测试评估大鼠社交行为。将GLS的过表达和干扰载体注射到自闭症大鼠杏仁核中,检测大鼠脑质量,杏仁核中谷氨酸含量及GLS蛋白的表达水平,评估大鼠社交行为。结果:丙戊酸钠诱导的自闭症大鼠脑质量增加,杏仁核中谷氨酸含量增加,SIRT2和GLS蛋白表达增加,促凋亡蛋白caspase-3表达增加,抗凋亡蛋白Bcl-2表达减少(均P<0.01)。与野生型大鼠比较,SIRT2^(–/–)大鼠的脑质量和杏仁核中谷氨酸含量减少,杏仁核中SIRT2和GLS蛋白表达水平降低,大鼠社交功能障碍改善(均P<0.01)。GLS过表达大鼠脑质量和杏仁核中谷氨酸含量增加,社交功能障碍加重(均P<0.01);抑制GLS表达则减少脑质量和杏仁核中谷氨酸含量,改善大鼠社交功能障碍(均P<0.01)。结论:丙戊酸钠诱导的自闭症大鼠杏仁核中谷氨酸循环系统异常,这种异常与SIRT2表达上调及其诱导的GLS产量增加有关;敲除SIRT2基因或抑制GLS的表达有助于维持谷氨酸循环平衡,改善大鼠社交行为障碍。Objective: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.Methods:Rat models of autism were established by maternal sodium valproic acid(VPA)exposure in wild-type rats and SIRT2-knockout(SIRT2^(–/–))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.Results: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(allP<0.01).Compared with the wild-type rats,SIRT2^(–/–)rats displayed decreased expression of SIRT2 and GLS proteins in the amygdala,reduced Glu content,and improved social dysfunction(allP<0.01).Overexpression of GLS increased brain weight and Glu content,and aggravated social dysfunction in VPA rats(allP<0.01).Knockdown of GLS decreased brain weight and Glu content,and improved social dysfunction in VPA rats(allP<0.01).Conclusions: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 outSIRT2gene or inhibiting the expression of GLS is helpful in maintaining the balanced glutamate cycle and in improving the social behavior disorder of rats.

关 键 词：自闭症 杏仁核 谷氨酸 谷氨酰胺酶 沉默信息调节因子2 社交行为 大鼠 

分 类 号：R741[医药卫生—神经病学与精神病学]