Corticostriatal dysfunction and social interaction deficits in mice lacking the cystine/glutamate antiporter.
Corticostriatal dysfunction and social interaction deficits in mice lacking the cystine/glutamate antiporter.
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缺乏胱氨酸/谷氨酸反向转运蛋白小鼠的皮质纹状体功能障碍和社会互动缺陷。
DOI：
10.1038/s41380-020-0751-3
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发表时间：
2021-09
影响因子：
11
通讯作者：
Massie A
中科院分区：
文献类型：
--
作者：
Bentea E;Villers A;Moore C;Funk AJ;O'Donovan SM;Verbruggen L;Lara O;Janssen P;De Pauw L;Declerck NB;DePasquale EAK;Churchill MJ;Sato H;Hermans E;Arckens L;Meshul CK;Ris L;McCullumsmith RE;Massie A
星形细胞胱氨酸/谷氨酸反转运系统xc -是中枢神经系统中细胞外谷氨酸的重要来源，对兴奋性神经传递有潜在影响。然而，它在脑生理学中的功能和重要性仍未完全了解。利用切片电生理学和具有xc -， xCT系统特定亚基基因缺失的小鼠（xCT - / -小鼠），我们发现皮质纹状体突触的神经传递减少。补充细胞外谷氨酸水平部分减轻了这种影响，这表明缺陷与细胞外谷氨酸可用性降低有关。我们观察到纹状体中棘神经元形态、树突棘密度、皮质纹状体突触密度和超微结构均未发生变化，表明所观察到的功能缺陷并非由于形态或结构异常所致。通过结合电子显微镜和谷氨酸免疫金标记，我们发现xCT - / -小鼠突触前终末、突触前线粒体和树突棘的细胞内谷氨酸密度降低。xCT - / -小鼠纹状体的蛋白质组学和运动组学显示突触前蛋白表达减少和激酶网络信号异常，这可能有助于观察到突触后反应的变化。最后，这些皮质纹状体失调导致xCT - / -小鼠的行为表型提示自闭症谱系障碍；在对皮质纹状体功能敏感的测试中，我们记录到重复挖掘行为增加，社交能力下降。总之，我们的研究结果表明，xc -系统在调节皮质纹状体神经传递和影响社会偏好和重复行为方面发挥了以前未被认识到的作用。
The astrocytic cystine/glutamate antiporter system xc− represents an important source of extracellular glutamate in the central nervous system, with potential impact on excitatory neurotransmission. Yet, its function and importance in brain physiology remain incompletely understood. Employing slice electrophysiology and mice with a genetic deletion of the specific subunit of system xc−, xCT (xCT−/− mice), we uncovered decreased neurotransmission at corticostriatal synapses. This effect was partly mitigated by replenishing extracellular glutamate levels, indicating a defect linked with decreased extracellular glutamate availability. We observed no changes in the morphology of striatal medium spiny neurons, the density of dendritic spines, or the density or ultrastructure of corticostriatal synapses, indicating that the observed functional defects are not due to morphological or structural abnormalities. By combining electron microscopy with glutamate immunogold labeling, we identified decreased intracellular glutamate density in presynaptic terminals, presynaptic mitochondria, and in dendritic spines of xCT−/− mice. A proteomic and kinomic screen of the striatum of xCT−/− mice revealed decreased expression of presynaptic proteins and abnormal kinase network signaling, that may contribute to the observed changes in postsynaptic responses. Finally, these corticostriatal deregulations resulted in a behavioral phenotype suggestive of autism spectrum disorder in the xCT−/− mice; in tests sensitive to corticostriatal functioning we recorded increased repetitive digging behavior and decreased sociability. To conclude, our findings show that system xc− plays a previously unrecognized role in regulating corticostriatal neurotransmission and influences social preference and repetitive behavior.
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影响因子：
4.6
作者：
Chutipongtanate S;Greis KD
通讯作者：
Greis KD
影响因子：
3.1
作者：
Aerts, Jeroen;Nys, Julie;Arckens, Lutgarde
通讯作者：
Arckens, Lutgarde
大鼠直接通路与间接通路纹状体投射神经元皮质输入差异的证据
影响因子：
5.3
作者：
Lei, WL;Jiao, Y;Reiner, A
通讯作者：
Reiner, A
影响因子：
14.8
作者：
Kalueff, Allan V.;Aldridge, J. Wayne;Tuohimaa, Pentti
通讯作者：
Tuohimaa, Pentti
影响因子：
3
作者：
Chen YW;Lin HC;Ng MC;Hsiao YH;Wang CC;Gean PW;Chen PS
通讯作者：
Chen PS