Mice lacking p35 display hyperactivity and paradoxical response to psychostimulants
Mice lacking p35 display hyperactivity and paradoxical response to psychostimulants
复制标题
DOI：
10.1111/j.1471-4159.2010.06748.x
复制
发表时间：
2010-07-01
影响因子：
4.7
通讯作者：
Paglini, Gabriela
中科院分区：
文献类型：
--
作者：
Ariel Krapacher, Favio;Cecilia Mlewski, Estela;Paglini, Gabriela
细胞周期蛋白依赖性激酶5/p35激酶复合物在多巴胺能神经传递中起关键作用。多巴胺（DA）信号的失调与神经和神经精神疾病有关。由于细胞周期蛋白依赖性激酶5（Cdk 5）需要与p35的适当激活，我们假设Cdk 5活性失调可能对纹状体介导的行为产生影响。我们使用了突变小鼠，p35蛋白（p35 KO）缺陷，表现出降低Cdk 5活性。在整个行为和生化特性的幼稚和精神兴奋剂治疗的小鼠，我们证明，只有青少年p35基因敲除小鼠表现出自发性活动过度，与矛盾hypolocomotor效应精神兴奋剂药物的反应，并表现出赤字适当的行为抑制。强有力的免疫标记酪氨酸羟化酶和高纹状体DA的合成和内容与低DA营业额，这是恢复精神兴奋剂，也被发现在突变小鼠。我们的研究结果表明，p35缺陷是关键参与了一个多动的行为表型与多巴胺能系统的功能亢进的表达，强调了正常的运动和情感功能的适当的Cdk 5激酶活性的重要性。因此，p35基因敲除小鼠可能是另一个有用的动物模型，了解细胞和分子事件的基础上注意缺陷多动障碍样疾病。
P>Cyclin-dependent kinase 5/p35 kinase complex plays a critical role in dopaminergic neurotransmission. Dysregulation of dopamine (DA) signaling is associated with neurological and neuropsychiatric disorders. As cyclin-dependent kinase 5 (Cdk5) requires association with p35 for its proper activation, we hypothesized that dysregulation of Cdk5 activity might have an effect on striatal-mediated behavior. We used a mutant mouse, deficient in p35 protein (p35 KO), which displayed reduced Cdk5 activity. Throughout behavioral and biochemical characterization of naive and psychostimulant-treated mice, we demonstrated that only juvenile p35 KO mice displayed spontaneous hyperactivity, responded with a paradoxical hypolocomotor effect to psychostimulant drugs and exhibited deficit on proper behavioral inhibition. Strong immunolabeling for tyrosine-hydroxylase and high striatal DA synthesis and contents with a low DA turnover, which were reverted by psychostimulants, were also found in mutant mice. Our results demonstrate that p35 deficiency is critically involved in the expression of a hyperactive behavioral phenotype with hyper-functioning of the dopaminergic system, emphasizing the importance of proper Cdk5 kinase activity for normal motor and emotional features. Thus, p35 KO mice may be another useful animal model for understanding cellular and molecular events underlying attention deficit hyperactivity disorder-like disorders.