Tabuchi Katsuhiko, Blundell Jacqueline, Etherton Mark R, Hammer Robert E, Liu Xinran, Powell Craig M, Südhof Thomas C
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Science. 2007 Oct 5;318(5847):71-6. doi: 10.1126/science.1146221. Epub 2007 Sep 6.
Autism spectrum disorders (ASDs) are characterized by impairments in social behaviors that are sometimes coupled to specialized cognitive abilities. A small percentage of ASD patients carry mutations in genes encoding neuroligins, which are postsynaptic cell-adhesion molecules. We introduced one of these mutations into mice: the Arg451-->Cys451 (R451C) substitution in neuroligin-3. R451C mutant mice showed impaired social interactions but enhanced spatial learning abilities. Unexpectedly, these behavioral changes were accompanied by an increase in inhibitory synaptic transmission with no apparent effect on excitatory synapses. Deletion of neuroligin-3, in contrast, did not cause such changes, indicating that the R451C substitution represents a gain-of-function mutation. These data suggest that increased inhibitory synaptic transmission may contribute to human ASDs and that the R451C knockin mice may be a useful model for studying autism-related behaviors.
自闭症谱系障碍（ASD）的特征是社交行为受损，有时还伴有特殊的认知能力。一小部分ASD患者在编码神经连接蛋白的基因中携带突变，神经连接蛋白是突触后细胞粘附分子。我们将其中一种突变引入小鼠：神经连接蛋白-3中的Arg451→Cys451（R451C）替换。R451C突变小鼠表现出社交互动受损，但空间学习能力增强。出乎意料的是，这些行为变化伴随着抑制性突触传递的增加，而对兴奋性突触没有明显影响。相比之下，神经连接蛋白-3的缺失并未引起此类变化，表明R451C替换代表功能获得性突变。这些数据表明，抑制性突触传递增加可能导致人类ASD，并且R451C基因敲入小鼠可能是研究自闭症相关行为的有用模型。
