Li Bo, Woo Ran-Sook, Mei Lin, Malinow Roberto
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Neuron. 2007 May 24;54(4):583-97. doi: 10.1016/j.neuron.2007.03.028.
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.
神经调节蛋白-1（NRG1）信号传导参与众多神经发育过程。通过连锁分析，nrg1已被证实与精神分裂症有关，但其病理生理作用尚不清楚。精神分裂症的主流模型认为谷氨酸能突触功能低下以及海马-皮质回路早期发育存在缺陷。在此，我们表明，作为NRG1的突触后靶点，erbB4受体在兴奋性突触结构和功能的活动依赖性成熟及可塑性中起关键作用。突触活动导致erbB4被激活并募集到突触中。过表达的erbB4选择性增强AMPA突触电流并增加树突棘大小。阻断NRG1/erbB4信号传导会使突触AMPA受体不稳定，并导致突触NMDA电流和树突棘丧失。我们的结果表明，NRG1/erbB4信号传导的基因缺陷会损害正常的活动驱动的谷氨酸能突触发育，导致谷氨酸能功能低下。这些发现将精神分裂症中提出的效应器联系起来：NRG / erbB4信号传导扰动、神经发育缺陷和谷氨酸能功能低下。
