Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Goettingen, Germany.
Cellular Neurophysiology, Hannover Medical School, Hannover, Germany.
Schizophr Bull. 2021 Aug 21;47(5):1409-1420. doi: 10.1093/schbul/sbab027.
The neuregulin 1 (NRG1) ErbB4 module is at the core of an "at risk" signaling pathway in schizophrenia. Several human studies suggest hyperstimulation of NRG1-ErbB4 signaling as a plausible pathomechanism; however, little is known about the significance of stage-, brain area-, or neural cell type-specific NRG1-ErbB4 hyperactivity for disease-relevant brain endophenotypes. To address these spatiotemporal aspects, we generated transgenic mice for Cre recombinase-mediated overexpression of cystein-rich domain (CRD) NRG1, the most prominent NRG1 isoform in the brain. A comparison of "brain-wide" vs cell type-specific CRD-NRG1 overexpressing mice revealed that pathogenic CRD-NRG1 signals for ventricular enlargement and neuroinflammation originate outside glutamatergic neurons and suggests a subcortical function of CRD-NRG1 in the control of body weight. Embryonic onset of CRD-NRG1 in glutamatergic cortical networks resulted in reduced inhibitory neurotransmission and locomotor hyperactivity. Our findings identify ventricular enlargement and locomotor hyperactivity, 2 main endophenotypes of schizophrenia, as specific consequences of spatiotemporally distinct expression profiles of hyperactivated CRD-NRG1 signaling.
神经调节蛋白 1（NRG1）ErbB4 模块是精神分裂症“风险”信号通路的核心。几项人类研究表明，NRG1-ErbB4 信号的过度刺激是一种合理的病理机制；然而，对于与疾病相关的脑内表型，NRG1-ErbB4 活性的阶段、脑区或神经细胞类型特异性的意义知之甚少。为了研究这些时空方面，我们生成了 Cre 重组酶介导的富含半胱氨酸结构域（CRD）NRG1 过表达的转基因小鼠，CRD-NRG1 是脑中最主要的 NRG1 亚型。“全脑”与细胞类型特异性 CRD-NRG1 过表达小鼠的比较表明，病理性 CRD-NRG1 信号导致脑室扩大和神经炎症起源于谷氨酸能神经元之外，并提示 CRD-NRG1 在体重控制中的皮质下功能。CRD-NRG1 在谷氨酸能皮质网络中的胚胎发生导致抑制性神经传递减少和运动过度活跃。我们的发现确定了脑室扩大和运动过度活跃，这是精神分裂症的 2 个主要内表型，作为过度激活的 CRD-NRG1 信号的时空特异性表达谱的特定后果。
