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Separable neural mechanisms for the pleiotropic association of copy number variants with neuropsychiatric traits.
Translational Psychiatry ( IF 6.8 ) Pub Date : 2020-03-13 , DOI: 10.1038/s41398-020-0771-4
Jonathan R Reinwald 1, 2 , Alexander Sartorius 1, 2 , Wolfgang Weber-Fahr 1 , Markus Sack 1 , Robert Becker 1 , Michael Didriksen 3 , Tine B Stensbøl 3 , Adam J Schwarz 4, 5, 6 , Andreas Meyer-Lindenberg 2 , Natalia Gass 1
Affiliation  

22q11.2, 15q13.3, and 1q21.1 microdeletions attract considerable interest by conferring high risk for a range of neuropsychiatric disorders, including schizophrenia and autism. A fundamental open question is whether divergent or convergent neural mechanisms mediate this genetic pleiotropic association with the same behavioral phenotypes. We use a combination of rodent microdeletion models with high-field neuroimaging to perform a comparative whole-brain characterization of functional and structural mechanisms linked to high-risk states. Resting-state functional and structural magnetic resonance imaging data were acquired on mice carrying heterozygous microdeletions in 22q11.2 (N = 12), 15q13.3 (N = 11), and 1q21.1 (N = 11) loci. We performed network-based statistic, graph, and morphometric analyses. The three microdeletions did not share significant systems-level features. Instead, morphometric analyses revealed microcephaly in 1q21.1 and macrocephaly in 15q13.3 deletions, whereas cerebellar volume was specifically reduced in 22q11.2 deletion. In function, 22q11.2 deletion mice showed widespread cortical hypoconnectivity, accompanied by opposing hyperconnectivity in dopaminergic pathways, which was confirmed by graph analysis. 1q21.1 exhibited distinct changes in posterior midbrain morphology and function, especially in periaqueductal gray, whereas 15q13.3 demonstrated alterations in auditory/striatal system. The combination of cortical hypoconnectivity and dopaminergic hyperconnectivity and reduced cerebellum in 22q11.2 deletion mirrors key neurodevelopmental features of schizophrenia, whereas changes in midbrain and auditory/striatal morphology and topology in 1q21.1 and 15q13.3 rather indicate focal processes possibly linked to the emergence of abnormal salience perception and hallucinations. In addition to insights into pathophysiological processes in these microdeletions, our results establish the general point that microdeletions might increase risk for overlapping neuropsychiatric phenotypes through separable neural mechanisms.



中文翻译:

副本数变体与神经精神学特征的多效性关联的独立神经机制。

22q11.2、15q13.3和1q21.1微缺失通过赋予一系列精神疾病(包括精神分裂症和自闭症)高风险,引起了人们的极大兴趣。一个基本的开放性问题是发散或收敛的神经机制是否以相同的行为表型介导这种遗传多效性关联。我们使用啮齿动物微缺失模型与高场神经影像学的组合来执行与高风险状态相关的功能和结构机制的比较全脑表征。在携带22q11.2(N  = 12),15q13.3(N  = 11)和1q21.1(N的杂合子微缺失的小鼠上获得静止状态的功能和结构磁共振成像数据 = 11)位点。我们执行了基于网络的统计,图形和形态计量分析。这三个微删除没有共享重要的系统级功能。取而代之的是,形态计量学分析显示1q21.1中有小头畸形,15q13.3中有大头畸形,而22q11.2缺失中小脑体积则特别减少。在功能上,22q11.2缺失小鼠表现出广泛的皮质低连接性,并伴随着多巴胺能途径中相反的高连接性,这通过图分析得到了证实。1q21.1表现出后中脑形态和功能的明显变化,尤其是在导水管周围的灰色中,而15q13.3则表现出听觉/纹状体系统的改变。皮质低连通性和多巴胺能高连通性的结合以及22q11时小脑的减少。2个缺失反映了精神分裂症的关键神经发育特征,而1q21.1和15q13.3中脑和听觉/纹状体形态和拓扑的变化则表明可能与异常显着性知觉和幻觉的出现有关的局灶性过程。除了深入了解这些微缺失的病理生理过程外,我们的研究结果还确定了一个普遍的观点,即微缺失可能通过可分离的神经机制增加重叠神经精神病学表型的风险。

更新日期:2020-03-13
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