Attention-deficit/hyperactivity phenotype in mice lacking the cyclin-dependent kinase 5 cofactor p35.
Attention-deficit/hyperactivity phenotype in mice lacking the cyclin-dependent kinase 5 cofactor p35.
复制标题
DOI：
10.1016/j.biopsych.2010.07.016
复制
发表时间：
2010-12-15
影响因子：
10.6
通讯作者：
Bibb, James A.
中科院分区：
文献类型：
--
作者：
Drerup, Justin M.;Hayashi, Kanehiro;Cui, Huxing;Mettlach, Gabriel L.;Long, Michael A.;Marvin, Marian;Sun, Xiankai;Goldberg, Matthew S.;Lutter, Michael;Bibb, James A.
注意力缺陷/多动障碍 (ADHD) 可能是由于皮质边缘回路建立延迟或多巴胺 (DA) 神经传递紊乱引起的。尽管广泛使用兴奋剂来治疗多动症，但人们对其对神经递质水平和新陈代谢的长期影响知之甚少。细胞周期蛋白依赖性激酶 5 (Cdk5) 通过控制合成、突触后反应和囊泡释放来调节 DA 信号传导。缺乏 Cdk5 激活辅因子 p35 的小鼠皮质层压有缺陷，这表明运动/奖励回路发生了改变。我们使用缺乏 p35 的小鼠来研究体内电路改变的影响。正电子发射断层扫描使用 2-脱氧-2-[18F]氟-D-葡萄糖作为放射性示踪剂测量大脑皮质中的葡萄糖代谢。逆行染料示踪和酪氨酸羟化酶免疫染色评估了 p35 敲除对内侧前额皮质 (PFC) 的影响，特别是与中脑边缘回路形成相关的影响。我们通过检查对精神兴奋剂的运动反应、单胺神经递质水平和 DA 信号转导来定义 Cdk5/p35 活性对儿茶酚胺能神经传递和运动活动的影响。在这里，我们报告说，缺乏 p35 的小鼠在长期注射可卡因或哌甲酯后，大脑皮层的葡萄糖摄取增加、基础过度活跃以及自相矛盾的运动减少。敲除小鼠在长期暴露于哌醋甲酯后，对 PFC 神经递质含量变化的敏感性也增加，并且急性纹状体和 PFC 切片中的基础 DAergic 活性发生改变。我们的研究结果表明，发育过程中 Cdk5/p35 活性的失调可能会导致 ADHD 病理学，如 p35 敲除小鼠的行为表型、中脑边缘回路建立不当以及纹状体和 PFC 儿茶酚胺能信号异常所示。
Attention-deficit/hyperactivity disorder (ADHD) may result from delayed establishment of corticolimbic circuitry or perturbed dopamine (DA) neurotransmission. Despite the widespread use of stimulants to treat ADHD, little is known regarding their long-term effects on neurotransmitter levels and metabolism. Cyclin-dependent kinase 5 (Cdk5) regulates DA signaling through control of synthesis, postsynaptic responses, and vesicle release. Mice lacking the Cdk5-activating cofactor p35 are deficient in cortical lamination, suggesting altered motor/reward circuitry. We employed mice lacking p35 to study the effect of altered circuitry in vivo. Positron emission tomography measured glucose metabolism in the cerebral cortex using 2-deoxy-2-[18F]fluoro-D-glucose as the radiotracer. Retrograde dye tracing and tyrosine hydroxylase immunostains assessed the effect of p35 knockout on the medial prefrontal cortex (PFC), especially in relation to mesolimbic circuit formation. We defined the influence of Cdk5/p35 activity on catecholaminergic neurotransmission and motor activity via examination of locomotor responses to psychostimulants, monoamine neurotransmitter levels, and DA signal transduction. Here, we report that mice deficient in p35 display increased glucose uptake in the cerebral cortex, basal hyperactivity, and paradoxical decreased locomotion in response to chronic injection of cocaine or methylphenidate. Knockout mice also exhibited an increased susceptibility to changes in PFC neurotransmitter content after chronic methylphenidate exposure, and altered basal DAergic activity in acute striatal and PFC slices. Our findings suggest that dysregulation of Cdk5/p35 activity during development may contribute to ADHD pathology, as indicated by the behavioral phenotype, improperly established mesolimbic circuitry, and aberrations in striatal and PFC catecholaminergic signaling in p35 knockout mice.
登录
查看更多内容
影响因子：
10.6
作者：
Jucaite, A;Fernell, E;Farde, L
通讯作者：
Farde, L
影响因子：
3.7
作者：
Hawasli AH;Koovakkattu D;Hayashi K;Anderson AE;Powell CM;Sinton CM;Bibb JA;Cooper DC
通讯作者：
Cooper DC
影响因子：
25
作者：
Hawasli, Ammar H.;Benavides, David R.;Bibb, James A.
通讯作者：
Bibb, James A.
DOI：
10.1023/a:1026201218296
发表时间：
1997-06-01
期刊：
Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists
影响因子：
--
作者：
Amen, D G;Carmichael, B D
通讯作者：
Carmichael, B D
DOI：
10.1097/00004583-199703000-00016
发表时间：
1997-03-01
影响因子：
13.3
作者：
Casey, BJ;Castellanos, FX;Rapoport, JL
通讯作者：
Rapoport, JL