RGS4 modulates serotonin signaling in prefrontal cortex and links to serotonin dysfunction in a rat model of schizophrenia
RGS4 modulates serotonin signaling in prefrontal cortex and links to serotonin dysfunction in a rat model of schizophrenia
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DOI：
10.1124/mol.106.032490
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发表时间：
2007-04-01
影响因子：
3.6
通讯作者：
Yan, Zhen
中科院分区：
文献类型：
--
作者：
Gu, Zhenglin;Jiang, Qian;Yan, Zhen
G蛋白信号转导调节因子4(RGS4)是近年来发现的与精神分裂症易感性相关的基因之一。然而，RGS4的功能以及它如何参与精神分裂症的病理生理学在很大程度上仍不清楚。在这项研究中，我们研究了RGS4对5-羟色胺和多巴胺受体功能的可能影响，这是治疗精神分裂症的两个主要靶点。5-羟色胺5-HT1a受体或多巴胺D-4受体的激活下调了前额叶皮质锥体神经元NMDAR通道的功能，NMDAR通道是控制认知和情绪的关键因素。阻断RGS4功能可显著增强5-HT1A对NMDAR电流的调节作用；反之，过表达RGS4可减弱5-HT1A的作用。相反，RGS4不改变D-4对NMDAR电流的调节。此外，亚慢性苯环利定(一种精神分裂症动物模型)治疗的大鼠PFC锥体神经元的5-HT1A受体的调节显著增强，这被发现与这些细胞中RGS4的表达特别减少有关。因此，我们的研究揭示了RGS4在皮质神经元中与5-羟色胺信号的重要偶联，并为RGS4潜在参与精神分裂症的病理生理提供了分子和细胞机制。
Regulator of G protein signaling 4 (RGS4) has recently been identified as one of the genes linked to the susceptibility of schizophrenia. However, the functional roles of RGS4 and how it may be involved in the pathophysiology of schizophrenia remain largely unknown. In this study, we investigated the possible impact of RGS4 on the function of serotonin and dopamine receptors, two main targets for schizophrenia treatment. Activation of serotonin 5-HT1A receptors or dopamine D-4 receptors down-regulates the function of NMDA receptor (NMDAR) channel, a key player controlling cognition and emotion, in pyramidal neurons of prefrontal cortex (PFC). Blocking RGS4 function significantly potentiated the 5-HT1A regulation of NMDAR current; conversely, overexpression of RGS4 attenuated the 5-HT1A effect. In contrast, the D-4 regulation of NMDAR current was not altered by RGS4 manipulation. Moreover, the 5-HT1A regulation of NMDA receptors was significantly enhanced in a subset of PFC pyramidal neurons from rats treated with subchronic phencyclidine, an animal model of schizophrenia, which was found to be associated with specifically decreased RGS4 expression in these cells. Thus, our study has revealed an important coupling of RGS4 to serotonin signaling in cortical neurons and provided a molecular and cellular mechanism underlying the potential involvement of RGS4 in the pathophysiology of schizophrenia.