Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain.
Nature. 2010 Apr 29;464(7293):1376-80. doi: 10.1038/nature08928. Epub 2010 Apr 14.
Schizophrenia is a complex disorder that interferes with the function of several brain systems required for cognition and normal social behaviour. Although the most notable clinical aspects of the disease only become apparent during late adolescence or early adulthood, many lines of evidence suggest that schizophrenia is a neurodevelopmental disorder with a strong genetic component. Several independent studies have identified neuregulin 1 (NRG1) and its receptor ERBB4 as important risk genes for schizophrenia, although their precise role in the disease process remains unknown. Here we show that Nrg1 and ErbB4 signalling controls the development of inhibitory circuitries in the mammalian cerebral cortex by cell-autonomously regulating the connectivity of specific GABA (gamma-aminobutyric acid)-containing interneurons. In contrast to the prevalent view, which supports a role for these genes in the formation and function of excitatory synapses between pyramidal cells, we found that ErbB4 expression in the mouse neocortex and hippocampus is largely confined to certain classes of interneurons. In particular, ErbB4 is expressed by many parvalbumin-expressing chandelier and basket cells, where it localizes to axon terminals and postsynaptic densities receiving glutamatergic input. Gain- and loss-of-function experiments, both in vitro and in vivo, demonstrate that ErbB4 cell-autonomously promotes the formation of axo-axonic inhibitory synapses over pyramidal cells, and that this function is probably mediated by Nrg1. In addition, ErbB4 expression in GABA-containing interneurons regulates the formation of excitatory synapses onto the dendrites of these cells. By contrast, ErbB4 is dispensable for excitatory transmission between pyramidal neurons. Altogether, our results indicate that Nrg1 and ErbB4 signalling is required for the wiring of GABA-mediated circuits in the postnatal cortex, providing a new perspective to the involvement of these genes in the aetiology of schizophrenia.
精神分裂症是一种复杂的疾病,它干扰了认知和正常社会行为所需的几个大脑系统的功能。尽管该疾病最显著的临床特征仅在青春期后期或成年早期出现,但许多证据表明精神分裂症是一种具有强烈遗传成分的神经发育障碍。几项独立的研究已经确定神经调节蛋白 1 (NRG1) 和其受体 ERBB4 是精神分裂症的重要风险基因,尽管它们在疾病过程中的确切作用仍然未知。在这里,我们表明 Nrg1 和 ErbB4 信号通过细胞自主调节特定 GABA(γ-氨基丁酸)含量中间神经元的连接,控制哺乳动物大脑皮层抑制性回路的发育。与普遍观点相反,普遍观点支持这些基因在锥体细胞之间兴奋性突触的形成和功能中发挥作用,我们发现 ErbB4 在小鼠新皮层和海马中的表达主要局限于某些类型的中间神经元。特别是,ErbB4 在许多表达 parvalbumin 的 Chandelier 和 Basket 细胞中表达,在这些细胞中,它定位于接收谷氨酸能输入的轴突末梢和突触后密度。体外和体内的增益和损失功能实验都表明,ErbB4 细胞自主地促进了轴突-轴突抑制性突触在锥体细胞上的形成,并且这种功能可能是由 Nrg1 介导的。此外,GABA 含量中间神经元中的 ErbB4 表达调节这些细胞树突上兴奋性突触的形成。相比之下,ErbB4 对于锥体神经元之间的兴奋性传递是可有可无的。总的来说,我们的结果表明,Nrg1 和 ErbB4 信号对于出生后皮层中 GABA 介导回路的布线是必需的,为这些基因参与精神分裂症的发病机制提供了一个新的视角。