【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。更多还原

【Abstract】 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.更多还原