Increased expression of dysbindin-1A leads to a selective deficit in NMDA receptor signaling in the hippocampus
Increased expression of dysbindin-1A leads to a selective deficit in NMDA receptor signaling in the hippocampus
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DOI：
10.1016/j.neuropharm.2011.08.007
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发表时间：
2011-12-01
影响因子：
4.7
通讯作者：
Emptage, Nigel
中科院分区：
文献类型：
--
作者：
Jeans, Alexander;Malins, Richard;Emptage, Nigel
主要精神分裂症易感基因疾病DTNBP 1对疾病风险的影响可能是通过基因产物dysbindin-1表达水平的变化介导的。然而，这些变化如何影响发病机制尚不清楚。最近的工作建立了改变dysbindin-1表达和N-甲基-D-天冬氨酸受体（NMDAR）表面水平变化之间的联系，提出了一种可能的机制，尽管这种关系的确切性质及其机制尚不清楚。使用大鼠海马的器官型切片，我们发现，dysbindin-1A在锥体神经元中的表达增加会导致NMDARs的严重和选择性功能减退，并阻断LTP的诱导。NMDAR的NR 1亚基的细胞表面而非细胞质表达降低，表明NMDAR运输失调，并且与此一致，网格蛋白依赖性内吞作用的药理学抑制足以逆转NMDAR信号传导的缺陷。这些结果支持了这样的想法，即质膜上的NMDAR水平受dysbindin-1表达变化的调节，并进一步深入了解dysbindin-1在精神分裂症中涉及的重要细胞通路中的作用。(C)2011爱思唯尔有限公司保留所有权利。
The effects of the major schizophrenia susceptibility gene disease DTNBP1 on disease risk are likely to be mediated through changes in expression level of the gene product, dysbindin-1. How such changes might influence pathogenesis is, however, unclear. One possible mechanism is suggested by recent work establishing a link between altered dysbindin-1 expression and changes in surface levels of N-methyl-D-aspartate receptors (NMDAR), although neither the precise nature of this relationship, nor the mechanism underlying it, are understood. Using organotypic slices of rat hippocampus, we show that increased expression of dysbindin-1A in pyramidal neurons causes a severe and selective hypofunction of NMDARs and blocks induction of LTP. Cell surface, but not cytoplasmic, expression of the NR1 subunit of the NMDAR is decreased, suggesting dysregulation of NMDAR trafficking and, consistent with this, pharmacological inhibition of clathrin-dependent endocytosis is sufficient to reverse the deficit in NMDAR signaling. These results support the idea that the level of the NMDAR at the plasma membrane is modulated by changes in dysbindin-1 expression and offer further insight into the role of dysbindin-1 at an important cellular pathway implicated in schizophrenia. (C) 2011 Elsevier Ltd. All rights reserved.