Bilsland James G, Wheeldon Alan, Mead Andrew, Znamenskiy Petr, Almond Sarah, Waters Kerry A, Thakur Matthew, Beaumont Vahri, Bonnert Timothy P, Heavens Robert, Whiting Paul, McAllister George, Munoz-Sanjuan Ignacio
Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme, The Neuroscience Research Centre, Essex, UK.
Neuropsychopharmacology. 2008 Feb;33(3):685-700. doi: 10.1038/sj.npp.1301446. Epub 2007 May 9.
The receptor tyrosine kinase product of the anaplastic lymphoma kinase (ALK) gene has been implicated in oncogenesis as a product of several chromosomal translocations, although its endogeneous role in the hematopoietic and neural systems has remained poorly understood. We describe that the generation of animals homozygous for a deletion of the ALK tyrosine kinase domain leads to alterations in adult brain function. Evaluation of adult ALK homozygotes (HOs) revealed an age-dependent increase in basal hippocampal progenitor proliferation and alterations in behavioral tests consistent with a role for this receptor in the adult brain. ALK HO animals displayed an increased struggle time in the tail suspension test and the Porsolt swim test and enhanced performance in a novel object-recognition test. Neurochemical analysis demonstrates an increase in basal dopaminergic signalling selectively within the frontal cortex. Altogether, these results suggest that ALK functions in the adult brain to regulate the function of the frontal cortex and hippocampus and identifies ALK as a new target for psychiatric indications, such as schizophrenia and depression, with an underlying deregulated monoaminergic signalling.
间变性淋巴瘤激酶（ALK）基因的受体酪氨酸激酶产物作为几种染色体易位的产物与肿瘤发生有关，尽管其在造血和神经系统中的内源性作用仍知之甚少。我们描述了缺失ALK酪氨酸激酶结构域的纯合动物的产生会导致成年脑功能改变。对成年ALK纯合子（HOs）的评估显示，基础海马祖细胞增殖随年龄增长而增加，行为测试中的改变表明该受体在成年大脑中发挥作用。ALK HO动物在悬尾试验和波索尔特游泳试验中的挣扎时间增加，在新物体识别试验中的表现增强。神经化学分析表明，额叶皮质内基础多巴胺能信号选择性增加。总之，这些结果表明，ALK在成年大脑中发挥作用以调节额叶皮质和海马体的功能，并将ALK确定为精神疾病（如精神分裂症和抑郁症）的新靶点，这些疾病存在潜在的单胺能信号失调。
