Bristow Greg C, Thomson David M, Openshaw Rebecca L, Mitchell Emma J, Pratt Judith A, Dawson Neil, Morris Brian J
Department of Biomedical and Life Sciences, University of Lancaster, Lancaster LA1 4YW, UK.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
Cell Rep. 2020 Apr 21;31(3):107536. doi: 10.1016/j.celrep.2020.107536.
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-amygdaloid-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.
16号染色体11.2区的重复显著增加了患精神分裂症的风险，但其机制仍 largely unknown。在这里，我们表明具有等效基因突变的小鼠（16p11.2重复小鼠）表现出海马-眶额叶和海马-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）在眶额叶皮质中的表达选择性降低，而生长抑素在外侧杏仁核中的表达降低。当在依赖海马-眶额叶连接的认知任务中对16p11.2重复小鼠进行测试时 在八臂迷宫“N-back”工作记忆任务和触摸屏持续操作任务中表现受损。与海马-杏仁核连接障碍一致，在与行为学相关的社会行为中也观察到缺陷。总体而言，细胞/分子、脑网络和行为改变明显反映了在精神分裂症患者中观察到的情况。此外，数据表明16p11.2重复选择性地影响海马-杏仁核-眶额叶回路，支持了这一新兴观点 该网络功能障碍是精神分裂症的核心要素，并为该疾病定义了一种神经回路内表型。
