Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects.
Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects.
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DOI：
10.1016/j.neuron.2015.11.023
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发表时间：
2016-01-06
期刊：
影响因子：
16.2
通讯作者：
Feng G
中科院分区：
文献类型：
--
作者：
Zhou Y;Kaiser T;Monteiro P;Zhang X;Van der Goes MS;Wang D;Barak B;Zeng M;Li C;Lu C;Wells M;Amaya A;Nguyen S;Lewis M;Sanjana N;Zhou Y;Zhang M;Zhang F;Fu Z;Feng G
遗传学研究显示，精神障碍之间的风险基因存在显著重叠。然而，目前还不清楚同一基因的不同突变如何导致不同的疾病。我们鉴定了两个突变小鼠系，这些小鼠带有与ASD和精神分裂症相关的Shank3突变。我们发现了共同的和不同的突触和行为表型。携带ASD连锁InsG3680突变的小鼠在断奶年龄之前就表现出纹状体突触传递缺陷和青少年社交能力受损，这与ASD症状的早期发作相吻合。另一方面，携带精神分裂症相关R1117X突变的成年小鼠在前额叶皮质和社会支配行为中显示出严重的突触缺陷。此外，我们还发现在这两个株系中Shank3基因的差异表达稳定，并上调了shank1/2的表达。这些数据表明，同一基因的不同等位基因在小鼠的分子、突触和回路水平上可能具有不同的表型，这可能有助于在人类患者中探索这些关系。
Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.