Molecular Basis of GABA Hypofunction in Adolescent Schizophrenia-Like Animals.
Molecular Basis of GABA Hypofunction in Adolescent Schizophrenia-Like Animals.
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青春期精神分裂症样动物 GABA 功能减退的分子基础
DOI：
10.1155/2021/9983438
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发表时间：
2021
影响因子：
3.1
通讯作者：
Cui D
中科院分区：
文献类型：
--
作者：
Wang X;Hu Y;Liu W;Ma Y;Chen X;Xue T;Cui D
精神分裂症是一种神经发育障碍，NMDA受体(NMDAR)功能低下似乎是中枢参与的。精神分裂症通常出现在青春期或成年早期。电生理和一些神经化学变化将GABA缺陷与NMDAR功能低下引起的异常行为联系在一起。然而，很少有研究系统地研究GABA缺陷的分子基础，特别是在青春期。为了解决这个问题，我们在PND 10给小鼠短暂地注射了MK-801，小鼠在青春期表现出精神分裂症相关的缺陷。脑片记录显示GABA传递减少，PVI+功能减退，提示GABA能功能减退。皮质蛋白质组学评估结合对Allen脑单细胞数据的分析表明，在兴奋性神经元、GABA能中间神经元和神经胶质细胞中，各种代谢过程在顶端都得到了丰富，并发生了差异变化。值得注意的是，在星形胶质细胞和中间神经元中，GABA相关的氨基酸代谢过程都受到了干扰，我们发现了一组下调的GABA相关蛋白(GAD65、SYNPR、DBI、GAT3、SN1和CPT1A)。它们协同调节GABA的合成、释放、重摄取和补充。它们的下调表明青春期GABA循环和动态平衡受到神经元-星形胶质细胞间通讯的调节。我们对GABA缺乏的分子基础的研究结果可能为早期预防和干预提供潜在的GABA能拯救药物靶点。
Schizophrenia is a neurodevelopmental disorder that NMDA receptor (NMDAR) hypofunction appears centrally involved. Schizophrenia typically emerges in adolescence or early adulthood. Electrophysiological and several neurochemical changes have linked the GABA deficits to abnormal behaviors induced by NMDAR hypofunction. However, few studies have systematically investigated the molecular basis of GABA deficits, especially during adolescence. To address this issue, we transiently administrated MK-801 to mice on PND 10, which exhibited schizophrenia-relevant deficits in adolescence. Slice recording showed reduced GABA transmission and PVI+ hypofunction, indicating GABAergic hypofunction. Cortical proteomic evaluation combined with analysis of single cell data from the Allen Brain showed that various metabolic processes were enriched in top ranks and differentially altered in excitatory neurons, GABAergic interneurons, and glial cells. Notably, the GABA-related amino acid metabolic process was disturbed in both astrocytes and interneurons, in which we found a downregulated set of GABA-related proteins (GAD65, SYNPR, DBI, GAT3, SN1, and CPT1A). They synergistically regulate GABA synthesis, release, reuptake, and replenishment. Their downregulation indicates impaired GABA cycle and homeostasis regulated by interneuron-astrocyte communication in adolescence. Our findings on molecular basis of GABA deficits could provide potential drug targets of GABAergic rescue for early prevention and intervention.
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影响因子：
3.7
作者：
Fredriksson, A;Archer, T
通讯作者：
Archer, T
影响因子：
3.4
作者：
Burke, Andrew R.;Miczek, Klaus A.
通讯作者：
Miczek, Klaus A.
DOI：
10.1037/h0077579
发表时间：
1979-01-01
期刊：
JOURNAL OF COMPARATIVE AND PHYSIOLOGICAL PSYCHOLOGY
影响因子：
--
作者：
BARNES, CA
通讯作者：
BARNES, CA
影响因子：
7.6
作者：
Heldt, SA;Green, A;Ressler, KJ
通讯作者：
Ressler, KJ
影响因子：
11
作者：
Glausier, J. R.;Fish, K. N.;Lewis, D. A.
通讯作者：
Lewis, D. A.