Over-stimulation of dopamine signaling is thought to underlie the pathophysiology of a list of mental disorders, such as psychosis, mania and attention-deficit/hyperactivity disorder. These disorders are frequently associated with cognitive deficits in attention or learning and memory, suggesting that persistent activation of dopamine signaling may change neural plasticity to induce cognitive or emotional malfunction. Dopamine transporter knockdown (DAT-KD) mice were used to mimic a hyper-dopamine state. Novel object recognition (NOR) task was performed to assess the recognition memory. To test the role of dopamine D3 receptor (D3R) on NOR, DAT-KD mice were treated with either a D3R antagonist, FAUC365 or by deletion of D3R. Total or phospho-GSK3 and –ERK1/2 signals in various brain regions were measured by Western blot analyses. To examine the impact of GSK3 signal on NOR, wild-type mice were systemically treated with GSK3 inhibitor SB216763 or, micro-injected with lentiviral shRNA of GSK3β or GSK3α in the medial prefrontal cortex (mPFC). We confirmed our previous findings that DAT-KD mice displayed a deficit in NOR memory, which could be prevented by deletion of D3R or exposure to FAUC365. In WT mice, p-GSK3α and p-GSK3β were significantly decreased in the mPFC after exposure to novel objects; however, the DAT-KD mice exhibited no such change in mPFC p-GSK3α/β levels. DAT-KD mice treated with FAUC365 or with D3R deletion exhibited restored novelty-induced GSK3 dephosphorylation in the mPFC. Moreover, inhibition of GSK3 in WT mice diminished NOR performance and impaired recognition memory. Lentiviral shRNA knockdown of GSK3β, but not GSK3α, in the mPFC of WT mice also impaired NOR. These findings suggest that D3R acts via GSK3β signaling in the mPFC to play a functional role in NOR memory. In addition, treatment with D3R antagonists may be a reasonable approach for ameliorating cognitive impairments or episodic memory deficits in bipolar disorder patients.

中文翻译：

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多巴胺D ₃受体和GSK3β信号介导多巴胺转运蛋白敲低小鼠内的新对象识别记忆的缺陷。

多巴胺信号传导的过度刺激被认为是一系列精神疾病（例如精神病，躁狂症和注意力缺乏/多动症）的病理生理基础。这些疾病通常与注意力或学习和记忆的认知缺陷有关，这表明多巴胺信号的持续激活可能改变神经可塑性，从而诱发认知或情绪障碍。使用多巴胺转运蛋白敲低（DAT-KD）小鼠模拟高多巴胺状态。执行新型对象识别（NOR）任务以评估识别内存。为了测试多巴胺D3受体（D3R）在NOR上的作用，将DAT-KD小鼠用D3R拮抗剂FAUC365或通过删除D3R进行处理。通过蛋白质印迹分析测量大脑各个区域的总或磷酸化GSK3和–ERK1 / 2信号。为了检查GSK3信号对NOR的影响，将野生型小鼠用GSK3抑制剂SB216763进行全身处理，或在内侧前额叶皮层（mPFC）中微注射GSK3β或GSK3α的慢病毒shRNA。我们证实了我们先前的发现，即DAT-KD小鼠的NOR记忆力不足，这可以通过删除D3R或暴露于FAUC365来预防。在野生型小鼠中，暴露于新物体后，mPFC中的p-GSK3α和p-GSK3β显着降低。然而，DAT-KD小鼠在mPFCp-GSK3α/β水平上没有表现出这种变化。用FAUC365或D3R缺失处理的DAT-KD小鼠在mPFC中表现出恢复的新颖性诱导的GSK3脱磷酸作用。此外，WT小鼠中GSK3的抑制会降低NOR的性能并削弱识别记忆。慢病毒shRNA的GSK3β，而不是GSK3α，WT小鼠的mPFC中的NOR也受损。这些发现表明，D3R通过mPFC中的GSK3β信号传导在NOR记忆中发挥功能性作用。此外，用D3R拮抗剂治疗可能是缓解双相情感障碍患者认知障碍或发作性记忆障碍的合理方法。