A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling.
A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling.
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DOI：
10.1038/ncomms8222
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发表时间：
2015-06-01
影响因子：
16.6
通讯作者：
Buonanno, Andres
中科院分区：
文献类型：
--
作者：
Vullhorst, Detlef;Mitchell, Robert M.;Keating, Carolyn;Roychowdhury, Swagata;Karavanova, Irina;Tao-Cheng, Jung-Hwa;Buonanno, Andres
神经调节蛋白受体ErbB4是GABA能中间神经元和神经网络同步化的重要调节因子。然而，人们对与ErbB4结合的内源性配体、激活它们的神经过程或它们的直接下游靶标知之甚少。在这里，我们证明，在培养的神经元和急性切片中，NMDA受体既是皮质中间神经元中神经调节蛋白2(NRG2)/ErbB4信号的效应者和靶点。中间神经元共表达ErbB4和NRG2，原NRG2聚集在隐窝顶端的细胞体上。NMDA受体的激活会迅速触发具有信号功能的NRG2胞外区的脱落。反过来，NRG2促进ErbB4与含有GluN2B的NMDA受体的联系，随后表面受体迅速内化，并有效下调NMDA，但不下调AMPA受体电流。这些作用选择性地发生在ErbB4阳性的中间神经元，而不是ErbB4阴性的锥体神经元。我们的发现揭示了ErbB4和NMDA受体之间的密切相互关系，可能对与精神障碍认知障碍相关的皮质微回路的调节有意义。神经调节蛋白受体ErbB4是GABA能中间神经元和神经网络同步化的重要调节器，但对与ErbB4及其下游靶点结合的内源性配体知之甚少。在这里，作者描述了在GABA能中间神经元中存在一种将NMDA受体活性与NRG信号联系起来的细胞自主双向通路。
The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization. However, little is known about the endogenous ligands that engage ErbB4, the neural processes that activate them or their direct downstream targets. Here we demonstrate, in cultured neurons and in acute slices, that the NMDA receptor is both effector and target of neuregulin 2 (NRG2)/ErbB4 signalling in cortical interneurons. Interneurons co-express ErbB4 and NRG2, and pro-NRG2 accumulates on cell bodies atop subsurface cisternae. NMDA receptor activation rapidly triggers shedding of the signalling-competent NRG2 extracellular domain. In turn, NRG2 promotes ErbB4 association with GluN2B-containing NMDA receptors, followed by rapid internalization of surface receptors and potent downregulation of NMDA but not AMPA receptor currents. These effects occur selectively in ErbB4-positive interneurons and not in ErbB4-negative pyramidal neurons. Our findings reveal an intimate reciprocal relationship between ErbB4 and NMDA receptors with possible implications for the modulation of cortical microcircuits associated with cognitive deficits in psychiatric disorders. The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization but little is known about the endogenous ligands that engage ErbB4 and the downstream targets. Here the authors describe the existence of a cell-autonomous bidirectional pathway that links NMDA receptor activity with NRG signalling in GABAergic interneurons.
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DOI：
10.1523/jneurosci.1815-08.2008
发表时间：
2008-07-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chen YJ;Johnson MA;Lieberman MD;Goodchild RE;Schobel S;Lewandowski N;Rosoklija G;Liu RC;Gingrich JA;Small S;Moore H;Dwork AJ;Talmage DA;Role LW
通讯作者：
Role LW
影响因子：
7.8
作者：
Bao, JX;Wolpowitz, D;Role, LW;Talmage, DA
通讯作者：
Talmage, DA
影响因子：
7.8
作者：
Henkart, M;Landis, D M;Reese, T S
通讯作者：
Reese, T S
影响因子：
3.8
作者：
Buonanno A
通讯作者：
Buonanno A
影响因子：
16.2
作者：
Huang, YZ;Won, S;Mei, L
通讯作者：
Mei, L