Program in Neuroscience, University of Maryland, Baltimore, MD 21201, USA.
Neuroscience. 2011 Mar 10;176:199-209. doi: 10.1016/j.neuroscience.2010.12.058. Epub 2010 Dec 31.
The largest structure of the basal ganglia, the striatum, modulates motor activity and cognitive function and is composed of GABAergic projection neurons and interneurons. To better understand the mechanisms underlying the development of the striatal neurons and their assembly into functional circuits, we used a mouse with a targeted conditional Met mutation in post-mitotic cells of the ventral telencephalon. Characterization of the ontogeny of the striatal neuronal populations demonstrated that disruption of Met signaling specifically altered the GABAergic interneurons. Medium spiny neurons (MSNs) and cholinergic interneurons were largely unaffected. Mice lacking Met signaling have increased numbers of striatal GABAergic interneurons in the lateral sensorimotor areas with distinct behavioral deficits. Motor function and memory formation and consolidation appeared intact, but procedural learning on the cued task of the Morris water maze was delayed. MET is a susceptibility gene in Tourette syndrome and autism, which are human disorders with impaired procedural learning. This study reveals how a striatal targeted disruption in Met signaling after generation of striatal neurons produces behavioral phenotypes shared by Tourette syndrome and autism, linking the human genetics with the mechanism underlying the disorders.
基底神经节中最大的结构纹状体，调节运动活动和认知功能，由 GABA 能投射神经元和中间神经元组成。为了更好地理解纹状体神经元发育及其组装成功能回路的机制，我们使用了一种在腹侧端脑的有丝分裂后细胞中具有靶向条件性 Met 突变的小鼠。纹状体神经元群体的发生特征表明，Met 信号的破坏特异性地改变了 GABA 能中间神经元。中型棘突神经元 (MSNs) 和胆碱能中间神经元受影响较小。缺乏 Met 信号的小鼠在外侧感觉运动区域的纹状体内 GABA 能中间神经元数量增加，且表现出明显的行为缺陷。运动功能、记忆形成和巩固似乎没有受到影响，但在莫瑞斯水迷宫的提示任务中的程序性学习延迟。MET 是抽动秽语综合征和自闭症的易感基因，这是两种人类疾病，存在程序性学习障碍。这项研究揭示了在纹状体神经元生成后，纹状体中 Met 信号的靶向破坏如何产生与抽动秽语综合征和自闭症共享的行为表型，将人类遗传学与疾病相关的机制联系起来。
