Neuregulin-1 Signals from the Periphery Regulate AMPA Receptor Sensitivity and Expression in GABAergic Interneurons in Developing Neocortex
Neuregulin-1 Signals from the Periphery Regulate AMPA Receptor Sensitivity and Expression in GABAergic Interneurons in Developing Neocortex
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DOI：
10.1523/jneurosci.3477-10.2011
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发表时间：
2011-04-13
影响因子：
5.3
通讯作者：
Nawa, Hiroyuki
中科院分区：
文献类型：
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作者：
Abe, Yuichi;Namba, Hisaaki;Nawa, Hiroyuki
神经调节蛋白-1（NRG 1）信号被认为有助于神经元发育和精神分裂症神经病理学。在这里，我们描述了过多的外周NRG 1信号对突触活动和AMPA受体表达的GABA能中间神经元在出生后啮齿动物新皮层的发育影响。将所有NRG 1变体共有的核心肽（eNRG 1）皮下给予小鼠幼仔。注射eNRG 1穿透血脑屏障并激活新皮质中的ErbB 4 NRG 1受体，其中ErbB 4 mRNA主要由小清蛋白阳性GABA能中间神经元表达。我们准备了新皮层切片的幼年小鼠，接受eNRG 1亚慢性和记录抑制性突触活动的第V层锥体神经元。出生后eNRG 1治疗显着增强多突触IPSC，虽然单突触IPSC不受影响。对含有小清蛋白的GABA能中间神经元的兴奋性输入的检查显示，eNRG 1处理显著增加AMPA触发的内向电流以及微型EPSC（mEPSC）的幅度和频率。在用可溶性全长形式的NRG 1 I型处理的小鼠中观察到对mEPSC的类似作用。与电生理学数据一致，AMPA受体GluA 1（即，GluR 1，GluRA）在eNRG 1处理的小鼠新皮质制备的突触后密度/细胞骨架部分中上调。与eNRG 1培养的皮质GABA能神经元在其树突上假定的突触部位表现出表面GluA 1免疫反应性的显着增加。这些结果表明，NRG 1循环在周边影响突触AMPA受体表达皮质GABA能中间神经元的出生后发展，并可能发挥作用的条件下，GABA相关的神经病理过程的特点。
Neuregulin-1 (NRG1) signaling is thought to contribute to both neuronal development and schizophrenia neuropathology. Here, we describe the developmental effects of excessive peripheral NRG1 signals on synaptic activity and AMPA receptor expression of GABAergic interneurons in postnatal rodent neocortex. A core peptide common to all NRG1 variants (eNRG1) was subcutaneously administered to mouse pups. Injected eNRG1 penetrated the blood-brain barrier and activated ErbB4 NRG1 receptors in the neocortex, in which ErbB4 mRNA is predominantly expressed by parvalbumin-positive GABAergic interneurons. We prepared neocortical slices from juvenile mice that were receiving eNRG1 subchronically and recorded inhibitory synaptic activity from layer V pyramidal neurons. Postnatal eNRG1 treatment significantly enhanced polysynaptic IPSCs, although monosynaptic IPSCs were not affected. Examination of excitatory inputs to parvalbumin-containing GABAergic interneurons revealed that eNRG1 treatment significantly increased AMPA-triggered inward currents and the amplitudes and frequencies of miniature EPSCs (mEPSCs). Similar effects on mEPSCs were observed in mice treated with a soluble, full-length form of NRG1 type I. Consistent with the electrophysiologic data, expression of the AMPA receptor GluA1 (i.e., GluR1, GluRA) was upregulated in the postsynaptic density/cytoskeletal fraction prepared from eNRG1-treated mouse neocortices. Cortical GABAergic neurons cultured with eNRG1 exhibited a significant increase in surface GluA1 immunoreactivity at putative synaptic sites on their dendrites. These results indicate that NRG1 circulating in the periphery influences postnatal development of synaptic AMPA receptor expression in cortical GABAergic interneurons and may play a role in conditions characterized by GABA-associated neuropathologic processes.