Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4401-6. doi: 10.1073/pnas.0915173107. Epub 2010 Feb 9.
Dopamine neurotransmission controls motor and perseverative behavior, is mediated by protein phosphorylation, and may be perturbed in disorders of attention and hyperactivity. To assess the role of casein kinase I (CK1) in the regulation of dopamine signaling, we generated a genetically modified mouse line that overexpresses CK1delta (CK1delta OE) specifically in the forebrain. Overexpression was confirmed both at the mRNA and at the protein levels. Under basal conditions, CK1delta OE mice exhibited horizontal and vertical hyperactivity, reduced anxiety, and nesting behavior deficiencies. The CK1delta OE mice also presented paradoxical responses to dopamine receptor stimulation, showing hypoactivity following injection of d-amphetamine or methylphenidate, indicating that CK1 activity has a profound effect on dopamine signaling in vivo. Interestingly, CK1delta overexpression led to significantly reduced D1R and D2R dopamine receptor levels. All together, under basal conditions and in response to drug stimulation, the behavioral phenotype of CK1delta OE mice is reminiscent of the symptoms and drug responses observed in attention-deficit/hyperactivity disorder and therefore the CK1delta OE mice appear to be a model for this disorder.
多巴胺神经传递控制运动和坚持行为，由蛋白质磷酸化介导，并且在注意力和多动症障碍中可能会受到干扰。为了评估酪蛋白激酶 I (CK1) 在多巴胺信号调节中的作用，我们生成了一种在大脑中特异性过表达 CK1delta (CK1delta OE) 的基因修饰小鼠品系。在 mRNA 和蛋白质水平上均证实了过表达。在基础条件下，CK1delta OE 小鼠表现出水平和垂直活动过度、焦虑减少和筑巢行为缺陷。CK1delta OE 小鼠对多巴胺受体刺激也表现出矛盾的反应，在注射安非他命或哌甲酯后表现出活动减少，表明 CK1 活性对体内多巴胺信号有深远影响。有趣的是，CK1delta 的过表达导致 D1R 和 D2R 多巴胺受体水平显著降低。总的来说，在基础条件下和对药物刺激的反应中，CK1delta OE 小鼠的行为表型类似于注意力缺陷多动障碍中观察到的症状和药物反应，因此 CK1delta OE 小鼠似乎是该疾病的模型。
