Role of dysbindin in dopamine receptor trafficking and cortical GABA function
Role of dysbindin in dopamine receptor trafficking and cortical GABA function
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DOI：
10.1073/pnas.0904289106
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发表时间：
2009-11-17
影响因子：
11.1
通讯作者：
Lu, Bai
中科院分区：
文献类型：
--
作者：
Ji, Yuanyuan;Yang, Feng;Lu, Bai
Dysbindin与精神分裂症的发病机制有关，但关于dysbindin如何影响精神病和相关行为回路中的神经元功能知之甚少。使用来自天然dysbindin突变体桑迪小鼠的dysbindin敲除系（dys（-/-）），我们探索了dysbindin在前额叶皮层（PFC）的多巴胺信号传导和神经元功能中的作用。结合细胞成像和生物化学实验显示，从dys（-/-）皮质神经元的细胞表面上的多巴胺受体D2，但不是D1的强劲增长。这是由于D2的再循环和插入增强，而不是内吞减少。dysbindin基因的破坏导致PFC和纹状体中的快速尖峰（FS）GABA能中间神经元的兴奋性显着下降。Dys（-/-）小鼠对PFC第V层锥体神经元的抑制性输入也减少。与野生型中间神经元相比，Dys（-/-）FS中间神经元中D2信号的增加与D2激动剂引起的神经元放电的更明显增加相关。总之，这些结果表明，dysbindin调节PFC功能，促进D2介导的GABA能功能的调制。
Dysbindin has been implicated in the pathogenesis of schizophrenia, but little is known about how dysbindin affects neuronal function in the circuitry underlying psychosis and related behaviors. Using a dysbindin knockout line (dys(-/-)) derived from the natural dysbindin mutant Sandy mice, we have explored the role of dysbindin in dopamine signaling and neuronal function in the prefrontal cortex (PFC). Combined cell imaging and biochemical experiments revealed a robust increase in the dopamine receptor D2, but not D1, on cell surface of neurons from dys(-/-) cortex. This was due to an enhanced recycling and insertion, rather than reduced endocytosis, of D2. Disruption of dysbindin gene resulted in a marked decrease in the excitability of fast-spiking (FS) GABA-ergic interneurons in both PFC and striatum. Dys(-/-) mice also exhibited a decreased inhibitory input to pyramidal neurons in layer V of PFC. The increased D2 signaling in dys(-/-) FS interneurons was associated with a more pronounced increase in neuronal firing in response to D2 agonist, compared to that in wild-type interneurons. Taken together, these results suggest that dysbindin regulates PFC function by facilitating D2-mediated modulation of GABAergic function.