Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, CA 94305, USA; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Stanford, CA 94305, USA.
Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, CA 94305, USA.
Cell. 2014 Jul 3;158(1):198-212. doi: 10.1016/j.cell.2014.04.045.
In humans, neuroligin-3 mutations are associated with autism, whereas in mice, the corresponding mutations produce robust synaptic and behavioral changes. However, different neuroligin-3 mutations cause largely distinct phenotypes in mice, and no causal relationship links a specific synaptic dysfunction to a behavioral change. Using rotarod motor learning as a proxy for acquired repetitive behaviors in mice, we found that different neuroligin-3 mutations uniformly enhanced formation of repetitive motor routines. Surprisingly, neuroligin-3 mutations caused this phenotype not via changes in the cerebellum or dorsal striatum but via a selective synaptic impairment in the nucleus accumbens/ventral striatum. Here, neuroligin-3 mutations increased rotarod learning by specifically impeding synaptic inhibition onto D1-dopamine receptor-expressing but not D2-dopamine receptor-expressing medium spiny neurons. Our data thus suggest that different autism-associated neuroligin-3 mutations cause a common increase in acquired repetitive behaviors by impairing a specific striatal synapse and thereby provide a plausible circuit substrate for autism pathophysiology.
在人类中，神经连接蛋白-3 突变与自闭症有关，而在老鼠中，相应的突变会产生强大的突触和行为改变。然而，不同的神经连接蛋白-3 突变在老鼠中导致的表型大不相同，而且没有因果关系将特定的突触功能障碍与行为改变联系起来。我们使用旋转轮运动学习作为老鼠获得性重复行为的替代指标，发现不同的神经连接蛋白-3 突变一致增强了重复运动习惯的形成。令人惊讶的是，神经连接蛋白-3 突变并非通过改变小脑或背侧纹状体，而是通过选择性地损害伏隔核/腹侧纹状体中的突触，导致这种表型。在这里，神经连接蛋白-3 突变通过特异性地阻碍 D1-多巴胺受体表达而不是 D2-多巴胺受体表达的中间神经元上的突触抑制，增加了旋转轮学习。因此，我们的数据表明，不同的自闭症相关神经连接蛋白-3 突变通过损害特定的纹状体突触导致获得性重复行为的共同增加，从而为自闭症的病理生理学提供了一个合理的电路基础。
