Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2
Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2
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DOI：
10.1038/nature11015
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发表时间：
2012-06-14
期刊：
影响因子：
64.8
通讯作者：
Boeckers, Tobias M.
中科院分区：
文献类型：
--
作者：
Schmeisser, Michael J.;Ey, Elodie;Boeckers, Tobias M.
自闭症谱系障碍包括一系列神经发育障碍，其特征是社交和沟通障碍以及重复行为（1）。在患有自闭症谱系障碍的患者中鉴定出突触蛋白如神经连接蛋白（2，3）、neurexins（4）、GKAP/SAPAP（5）和ProSAP/Shanks（6-10）中的突变，但致病机制在很大程度上仍然未知。ProSAP/Shanks在兴奋性突触处构建大的同源和异源蛋白质复合物，并以层状方式组织突触后密度的复杂蛋白质机制（11，12）。在这里，我们证明了ProSAP 1/Shank 2的基因缺失导致突触处离子型谷氨酸受体的早期脑区域特异性上调和ProSAP 2/Shank 3水平的增加。此外，ProSAP 1/Shank 2（-/-）突变体表现出更少的树突棘，并显示减少的基础突触传递，减少的频率的微型兴奋性突触后电流和增强的N-甲基-D-天冬氨酸受体介导的兴奋性电流在生理水平。突变体极度活跃，表现出深刻的自闭症样行为改变，包括重复梳理以及声音和社会行为的异常。通过比较ProSAP 1/Shank 2（-/-）突变体与ProSAP 2/Shank 3 α β（-/-）小鼠的数据，我们发现突触谷氨酸受体表达的不同异常可导致社会互动和交流的改变。因此，我们建议自闭症谱系障碍的适当治疗应仔细匹配潜在的突触病变表型。
Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour(1). Mutations in synaptic proteins such as neuroligins(2,3), neurexins(4), GKAPs/SAPAPs(5) and ProSAPs/Shanks(6-10) were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo-and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion(11,12). Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-D-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3 alpha beta(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.