The critical balance between dopamine D2 receptor and RGS for the sensitive detection of a transient decay in dopamine signal.
The critical balance between dopamine D2 receptor and RGS for the sensitive detection of a transient decay in dopamine signal.
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多巴胺D2受体和RGS之间的临界平衡，用于灵敏地检测多巴胺信号中的瞬时衰减。
DOI：
10.1371/journal.pcbi.1009364
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发表时间：
2021-09
影响因子：
4.3
通讯作者：
Ishii S
中科院分区：
文献类型：
--
作者：
Urakubo H;Yagishita S;Kasai H;Kubota Y;Ishii S
在行为学习中，奖励相关事件被编码成大脑中的相位多巴胺（DA）信号。特别是，意外的奖励遗漏导致纹状体中DA的阶段性减少（DA下降），这触发了表达DA D2受体（D2 R）的棘投射神经元（D2 SPN）的长时程增强（LTP）。虽然这种LTP是奖赏辨别所必需的，但目前尚不清楚如此短的DA下降信号（0.5-2 s）如何通过细胞内信号传递到重合检测器腺苷酸环化酶（AC）。在本研究中，我们建立了一个计算模型的D2信号，以确定条件的DA下降检测。只有当基础DA信号充分抑制AC并且DA下降信号充分解除抑制AC时，才可以检测到DA下降。我们发现，只有当两个关键分子，D2 R和G蛋白信号转导（RGS）的调节剂在一定范围内平衡时，这两个要求才能同时得到满足;这种平衡确实在实验研究中观察到。我们还发现，需要高水平的RGS检测0.5秒的短DA下降，这些要求的分析解决方案证实了它们的普遍性。D2 R和RGS之间的失衡与精神分裂症和DYT 1肌张力障碍有关，这两种疾病都伴有异常的纹状体LTP。我们的模拟表明，精神分裂症和DYT 1肌张力障碍患者的D2 SPN不能检测短DA骤降。我们最后讨论了这种精神和运动障碍可以理解为D2 R和RGS之间的不平衡。在我们的大脑中，学习和记忆受到多巴胺（DA）信号的强烈调节。即使是短暂的DA缺失（0.5-2秒），称为“DA下降”，也会触发长期记忆的形成，其潜在过程迄今为止在很大程度上是未知的。在这里，我们研究了DA骤降如何通过生化信号网络处理以产生长期记忆。计算机模拟和理论分析表明，只有当两个关键分子，DA D2受体（D2 R）和G蛋白信号调节因子（RGS）的水平都微妙平衡时，DA-dip信号才能被处理。这种平衡似乎在健康的大脑中实现，而D2 R和RGS水平之间的不平衡出现在精神分裂症和DYT 1肌张力障碍患者中，这两者都可能表现出异常的长期记忆。D2 R-RGS失衡妨碍DA-下降的可检测性，从而干扰长期记忆的形成，这可能导致精神分裂症和肌张力障碍的症状。D2 R和RGS之间的平衡似乎在健康的大脑中受到精细调节，以支持正常的学习和记忆。
In behavioral learning, reward-related events are encoded into phasic dopamine (DA) signals in the brain. In particular, unexpected reward omission leads to a phasic decrease in DA (DA dip) in the striatum, which triggers long-term potentiation (LTP) in DA D2 receptor (D2R)-expressing spiny-projection neurons (D2 SPNs). While this LTP is required for reward discrimination, it is unclear how such a short DA-dip signal (0.5–2 s) is transferred through intracellular signaling to the coincidence detector, adenylate cyclase (AC). In the present study, we built a computational model of D2 signaling to determine conditions for the DA-dip detection. The DA dip can be detected only if the basal DA signal sufficiently inhibits AC, and the DA-dip signal sufficiently disinhibits AC. We found that those two requirements were simultaneously satisfied only if two key molecules, D2R and regulators of G protein signaling (RGS) were balanced within a certain range; this balance has indeed been observed in experimental studies. We also found that high level of RGS was required for the detection of a 0.5-s short DA dip, and the analytical solutions for these requirements confirmed their universality. The imbalance between D2R and RGS is associated with schizophrenia and DYT1 dystonia, both of which are accompanied by abnormal striatal LTP. Our simulations suggest that D2 SPNs in patients with schizophrenia and DYT1 dystonia cannot detect short DA dips. We finally discussed that such psychiatric and movement disorders can be understood in terms of the imbalance between D2R and RGS. In our brain, learning and memory are strongly modulated by dopamine (DA) signals. Even a short absence of DA (0.5–2 s), called “DA dip,” triggers long-term memory formation, the underlying processes of which are hitherto largely unknown. Here, we examined how the DA dips are processed through a biochemical signaling network to generate long-term memory. Computer simulation and theoretical analyses showed that the DA-dip signal is processed only if the levels of two key molecules, DA D2 receptor (D2R) and regulators of G protein signaling (RGS), are both delicately balanced. This balance seems to be achieved in the healthy brain, whereas imbalance between D2R and RGS levels appear in patients with schizophrenia and DYT1 dystonia, both of which may manifest abnormal long-term memory. The D2R–RGS imbalances hamper DA-dip detectability, and thus disturb long-term memory formation, which may result in the symptoms of schizophrenia and dystonia. The balance between D2R and RGS appear to be finely regulated in the healthy brain to underpin normal learning and memory.
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