16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia
16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia
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DOI：
10.1016/j.celrep.2020.107536
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发表时间：
2020-04-21
期刊：
影响因子：
8.8
通讯作者：
Morris, Brian J.
中科院分区：
文献类型：
--
作者：
Bristow, Greg C.;Thomson, David M.;Morris, Brian J.
染色体16p11.2的重复极大地增加了患精神分裂症的风险，但其机制在很大程度上仍不清楚。在这里，我们显示了具有相同基因突变的小鼠(16p11.2重复小鼠)表现出海马体-眶前叶和海马体-杏仁核功能连接受损。与精神分裂症相关的GABA能细胞标志物(小白蛋白和钙结合蛋白)在眶前叶皮质的表达选择性降低，而生长抑素在杏仁外侧核的表达降低。当16p11.2重复小鼠在依赖于海马-眼眶前额连接的认知任务中被测试时，在8臂迷宫工作记忆任务和触摸屏连续操作任务中的表现受到损害。与海马-杏仁核连接障碍一致，也观察到与行为学相关的社会行为缺陷。总体而言，细胞/分子、脑网络和行为变化明显反映了精神分裂症患者的观察结果。此外，数据表明，16p11.2重复选择性地影响海马区-杏仁-达洛样区-眼眶额部回路，支持该网络功能障碍是精神分裂症的核心因素的新兴观点，并定义了该疾病的神经回路内表型。
Chromosome 16p11.2 duplications dramatically increase risk for schizophrenia, but the mechanisms remain largely unknown. Here, we show that mice with an equivalent genetic mutation (16p11.2 duplication mice) exhibit impaired hippocampal-orbitofrontal and hippocampal-amygdala functional connectivity. Expression of schizophrenia-relevant GABAergic cell markers (parvalbumin and calbindin) is selectively decreased in orbitofrontal cortex, while somatostatin expression is decreased in lateral amygdala. When 16p11.2 duplication mice are tested in cognitive tasks dependent on hippocampal-orbitofrontal connectivity, performance is impaired in an 8-arm maze "N-back" working memory task and in a touchscreen continuous performance task. Consistent with hippocampal-amygdala dysconnectivity, deficits in ethologically relevant social behaviors are also observed. Overall, the cellular/molecular, brain network, and behavioral alterations markedly mirror those observed in schizophrenia patients. Moreover, the data suggest that 16p11.2 duplications selectively impact hippocampal-amyg-daloid-orbitofrontal circuitry, supporting emerging ideas that dysfunction in this network is a core element of schizophrenia and defining a neural circuit endophenotype for the disease.