The neuregulin-1 receptor ErbB4 controls Glutamatergic synapse maturation and plasticity
The neuregulin-1 receptor ErbB4 controls Glutamatergic synapse maturation and plasticity
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DOI：
10.1016/j.neuron.2007.03.028
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发表时间：
2007-05-24
期刊：
影响因子：
16.2
通讯作者：
Malinow, Roberto
中科院分区：
文献类型：
--
作者：
Li, Bo;Woo, Ran-Sook;Malinow, Roberto
Neuregulin-1 (NRG1) 信号传导参与许多神经发育过程。通过连锁分析，nrg1 已与精神分裂症相关，尽管其病理生理作用尚不清楚。流行的精神分裂症模型涉及谷氨酸突触功能减退和海马皮质回路早期发育缺陷。在这里，我们证明 erbB4 受体作为 NRG1 的突触后靶标，在兴奋性突触结构和功能的活动依赖性成熟和可塑性中发挥关键作用。突触活动导致 erbB4 激活并招募到突触中。过度表达的 erbB4 选择性增强 AMPA 突触电流并增加树突棘大小。阻止 NRG1/erbB4 信号传导会破坏突触 AMPA 受体的稳定性，并导致突触 NMDA 电流和棘的丧失。我们的结果表明，正常活动驱动的谷氨酸突触发育受到 NRG1/erbB4 信号传导遗传缺陷的损害，导致谷氨酸能功能减退。这些发现将精神分裂症中提出的效应器联系起来：NRG1/erbB4 信号传导扰动、神经发育缺陷和谷氨酸能功能减退。
Neuregulin-1 (NRG1) signaling participates in numerous neurodevelopmental processes. Through linkage analysis, nrg1 has been associated with schizophrenia, although its pathophysiological role is not understood. The prevailing models of schizophrenia invoke hypofunction of the glutamatergic synapse and defects in early development of hippocampal-cortical circuitry. Here, we show that the erbB4 receptor, as a postsynaptic target of NRG1, plays a key role in activity-dependent maturation and plasticity of excitatory synaptic structure and function. Synaptic activity leads to the activation and recruitment of erbB4 into the synapse. Overexpressed erbB4 selectively enhances AMPA synaptic currents and increases dendritic spine size. Preventing NRG1/erbB4 signaling destabilizes synaptic AMPA receptors and leads to loss of synaptic NMDA currents and spines. Our results indicate that normal activity-driven glutamatergic synapse development is impaired by genetic deficits in NRG1/erbB4 signaling leading to glutamatergic hypofunction. These findings link proposed effectors in schizophrenia: NRG1/erbB4 signaling perturbation, neurodevelopmental deficit, and glutamatergic hypofunction.