Activation of mGluR2/3 underlies the effects of N-acetylcystein on amygdala-associated autism-like phenotypes in a valproate-induced rat model of autism.
Activation of mGluR2/3 underlies the effects of N-acetylcystein on amygdala-associated autism-like phenotypes in a valproate-induced rat model of autism.
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DOI：
10.3389/fnbeh.2014.00219
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发表时间：
2014
影响因子：
3
通讯作者：
Chen PS
中科院分区：
文献类型：
--
作者：
Chen YW;Lin HC;Ng MC;Hsiao YH;Wang CC;Gean PW;Chen PS
暴露于丙戊酸盐（VPA）的雄性后代中的自闭症样表型与丘脑-杏仁核通路中的高多巴胺能神经传递相关。胶质细胞胱氨酸/谷氨酸交换（XC-系统），将细胞外胱氨酸交换为细胞内谷氨酸，在细胞外谷氨酸的维持中起着重要作用。N-乙酰半胱氨酸（NAC）是一种胱氨酸前药，通过刺激系统XC−恢复细胞外谷氨酸。在这项研究中，我们研究了NAC对自闭症样表型和丘脑-杏仁核突触神经传递的影响，以及代谢型谷氨酸受体2/3（mGluR 2/3）的参与。丙戊酸盐给药大鼠在E12.5接受500 mg/kg NaVPA单次腹膜内注射。在出生后第21天（P21），给予NAC或生理盐水，每天一次，共10天。从第8天到第10天，在行为测试之前1/2小时给予NAC。长期给予NAC恢复了VPA暴露后代的社会互动的持续时间和频率，并改善了焦虑样行为。在杏仁核切片中，NAC处理使mEPSC频率增加正常化，并降低VPA暴露诱导的成对脉冲易化（PPF）。NAC对VPA暴露后代的社会互动和焦虑样行为的影响在杏仁核内输注mGluR 2/3拮抗剂LY 341495后被阻断。VPA暴露组子代mGluR 2/3蛋白和mGluR 2 mRNA表达均显著降低。相比之下，mGluR 3的mRNA水平之间没有不同的盐水和VPA暴露的后代。这些结果提供了第一个证据表明，VPA暴露后代的社会互动和增强的突触前兴奋性传递的破坏可以被NAC拯救，这取决于mGluR 2/3的激活。
Autism-like phenotypes in male valproate (VPA)-exposed offspring have been linked to high glutamatergic neurotransmission in the thalamic-amygdala pathway. Glial cystine/glutamate exchange (system Xc−), which exchanges extracellular cystine for intracellular glutamate, plays a significant role in the maintenance of extracellular glutamate. N-acetylcysteine (NAC) is a cystine prodrug that restores extracellular glutamate by stimulating system Xc−. In this study, we examined the effects of NAC on autism-like phenotypes and neurotransmission in the thalamic–amygdala synapses, as well as the involvement of metabotropic glutamate receptors 2/3 (mGluR2/3). Valproate-treated rats received a single intraperitoneal injection of 500 mg/kg NaVPA on E12.5. On postnatal day 21 (P21), NAC or saline was administered once daily for 10 days. From day 8 to 10, NAC was given 1/2 h prior to behavioral testing. Chronic administration of NAC restored the duration and frequency of social interaction and ameliorated anxiety-like behaviors in VPA-exposed offspring. In amygdala slices, NAC treatment normalized the increased frequency of mEPSCs and decreased the paired pulse facilitation (PPF) induced by VPA exposure. The effects of NAC on social interaction and anxiety-like behavior in the VPA-exposed offspring were blocked after intra-amygdala infusion of mGluR2/3 antagonist LY341495. The expressions of mGluR2/3 protein and mGluR2 mRNA were significantly lower in the VPA-exposed offspring. In contrast, the mGluR3 mRNA level did not differ between the saline- and VPA-exposed offspring. These results provide the first evidence that the disruption of social interaction and enhanced presynaptic excitatory transmission in VPA-exposed offspring could be rescued by NAC, which depends on the activation of mGluR2/3.
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影响因子：
3.7
作者：
Foley KA;Ossenkopp KP;Kavaliers M;Macfabe DF
通讯作者：
Macfabe DF
影响因子：
4.2
作者：
Khan, M;Sekhon, B;Singh, AK
通讯作者：
Singh, AK
影响因子：
14.5
作者：
Bailey, A;Luthert, P;Lantos, P
通讯作者：
Lantos, P
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Hadjikhani, Nouchine;Joseph, Robert M.;Tager-Flusberg, Helen
通讯作者：
Tager-Flusberg, Helen