Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling
Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling
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DOI：
10.1038/nature08928
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发表时间：
2010-04-29
期刊：
影响因子：
64.8
通讯作者：
Rico, Beatriz
中科院分区：
文献类型：
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作者：
Fazzari, Pietro;Paternain, Ana V.;Rico, Beatriz
精神分裂症是一种复杂的疾病，会干扰认知和正常社会行为所需的多个大脑系统的功能。尽管该疾病最显着的临床特征仅在青春期晚期或成年早期才变得明显，但许多证据表明精神分裂症是一种具有很强遗传成分的神经发育障碍(1,2)。几项独立研究已确定神经调节蛋白 1 (NRG1) 及其受体 ERBB4 是精神分裂症的重要风险基因(3,4)，尽管它们在疾病过程中的确切作用仍不清楚。在这里，我们发现 Nrg1 和 ErbB4 信号传导通过细胞自主调节含有特定 GABA（γ-氨基丁酸）的中间神经元的连接来控制哺乳动物大脑皮层中抑制电路的发育。流行的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的作用，与此相反，我们发现小鼠新皮质和海马中的 ErbB4 表达很大程度上局限于某些类型的中间神经元。特别是，ErbB4 由许多表达小白蛋白的吊灯细胞和篮细胞表达，它定位于轴突末端和接受谷氨酸能输入的突触后密度。体外和体内的功能获得和丧失实验表明，ErbB4 细胞自主促进锥体细胞上轴突抑制性突触的形成，并且该功能可能由 Nrg1 介导。此外，含有 GABA 的中间神经元中的 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来说是可有可无的。总而言之，我们的结果表明 Nrg1 和 ErbB4 信号传导对于出生后皮质中 GABA 介导的回路的连接是必需的，这为这些基因参与精神分裂症的病因学提供了新的视角。
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(1,2). Several independent studies have identified neuregulin 1 (NRG1) and its receptor ERBB4 as important risk genes for schizophrenia(3,4), 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.