School of Life Sciences, Nanchang University, Nanchang, 330031, China.
Institute of Life Science, Nanchang University, Nanchang, 330031, China.
Cell Death Dis. 2021 Apr 14;12(4):403. doi: 10.1038/s41419-021-03687-8.
The genes encoding for neuregulin1 (NRG1), a growth factor, and its receptor ErbB4 are both risk factors of major depression disorder and schizophrenia (SZ). They have been implicated in neural development and synaptic plasticity. However, exactly how NRG1 variations lead to SZ remains unclear. Indeed, NRG1 levels are increased in postmortem brain tissues of patients with brain disorders. Here, we studied the effects of high-level NRG1 on dendritic spine development and function. We showed that spine density in the prefrontal cortex and hippocampus was reduced in mice (ctoNrg1) that overexpressed NRG1 in neurons. The frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced in both brain regions of ctoNrg1 mice. High expression of NRG1 activated LIMK1 and increased cofilin phosphorylation in postsynaptic densities. Spine reduction was attenuated by inhibiting LIMK1 or blocking the NRG1-LIMK1 interaction, or by restoring NRG1 protein level. These results indicate that a normal NRG1 protein level is necessary for spine homeostasis and suggest a pathophysiological mechanism of abnormal spines in relevant brain disorders.
神经调节蛋白 1（NRG1）是一种生长因子，其编码基因和其受体 ErbB4 都是重度抑郁症和精神分裂症（SZ）的风险因素。它们参与神经发育和突触可塑性。然而，NRG1 变异如何导致 SZ 仍不清楚。事实上，NRG1 水平在患有脑部疾病的患者的脑组织中增加。在这里，我们研究了高水平 NRG1 对树突棘发育和功能的影响。我们表明，在神经元中过度表达 NRG1 的小鼠（ctoNrg1）的前额叶皮层和海马体中的棘突密度降低。ctoNrg1 小鼠的两个脑区的微小兴奋性突触后电流（mEPSC）频率降低。NRG1 的高表达激活 LIMK1 并增加突触后密度中的丝切蛋白磷酸化。通过抑制 LIMK1 或阻断 NRG1-LIMK1 相互作用，或通过恢复 NRG1 蛋白水平，可减轻棘突减少。这些结果表明，正常的 NRG1 蛋白水平对于棘突稳态是必要的，并提示了相关脑部疾病中异常棘突的病理生理学机制。
