Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
Transl Psychiatry. 2020 Mar 13;10(1):93. doi: 10.1038/s41398-020-0771-4.
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.
22q11.2、15q13.3 和 1q21.1 微缺失引起了相当大的关注，因为它们会增加一系列神经精神疾病的风险，包括精神分裂症和自闭症。一个基本的开放性问题是，不同的或趋同的神经机制是否介导了这种与相同行为表型的遗传多效性关联。我们使用带有高场神经影像学的啮齿动物微缺失模型组合，对与高风险状态相关的功能和结构机制进行全面的全脑特征描述。对携带 22q11.2（N=12）、15q13.3（N=11）和 1q21.1（N=11）杂合性微缺失的小鼠进行静息态功能和结构磁共振成像数据采集。我们进行了基于网络的统计学、图形和形态计量学分析。这三个微缺失没有共享显著的系统水平特征。相反，形态计量学分析显示 1q21.1 微缺失存在小头畸形，15q13.3 微缺失存在大头畸形，而 22q11.2 微缺失则导致小脑体积特异性减小。在功能上，22q11.2 微缺失小鼠表现出广泛的皮质连接不足，同时多巴胺能通路存在相反的连接过度，这通过图形分析得到了证实。1q21.1 表现出中脑后部形态和功能的明显变化，特别是在导水管周围灰质，而 15q13.3 则表现出听觉/纹状体系统的改变。22q11.2 微缺失的皮质连接不足和多巴胺能连接过度以及小脑减小的组合，反映了精神分裂症的关键神经发育特征，而 1q21.1 和 15q13.3 中中脑和听觉/纹状体的形态和拓扑结构的变化则表明可能与异常突显感知和幻觉出现相关的局部过程。除了对这些微缺失的病理生理过程的深入了解之外，我们的结果还确立了一个普遍观点，即微缺失可能通过可分离的神经机制增加重叠的神经精神表型的风险。
