The Schizophrenia Susceptibility Gene OPCML Regulates Spine Maturation and Cognitive Behaviors through Eph-Cofilin Signaling
The Schizophrenia Susceptibility Gene OPCML Regulates Spine Maturation and Cognitive Behaviors through Eph-Cofilin Signaling
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精神分裂症易感基因 OPCML 通过 Eph-Cofilin 信号调节脊柱成熟和认知行为
DOI：
10.1016/j.celrep.2019.08.091
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发表时间：
2019
期刊：
影响因子：
8.8
通讯作者：
Zhang Dai
中科院分区：
文献类型：
--
作者：
Zhang Zhengrong;Ye Maoqing;Li Qiongwei;You Yang;Yu Hao;Ma Yuanlin;Mei Liwei;Sun Xiaqin;Wang Lifang;Yue Weihua;Li Rena;Li Jun;Zhang Dai
以前的遗传学和生物学证据都集中在精神分裂症与突触功能障碍的关系上，据报道，编码突触膜蛋白的OPCML与精神分裂症有关。然而，它在精神分裂症的病理生理学中的作用在很大程度上仍不清楚。在这里，我们发现OpcML在小鼠的海马区有强烈的表达；消融OpcML会导致磷酸化的cofilin减少和F-肌动蛋白动力学失调，从而干扰脊柱的成熟。此外，OpcML与EphB2相互作用，通过调节ePhin-EphB2-cofilin信号通路来控制脊柱的稳定性。OpcML缺陷小鼠表现出认知行为受损和感觉运动门控异常，这与精神分裂症等神经精神疾病的特征相似。值得注意的是，给药阿立哌唑通过增加磷酸化Cofilin水平和促进脊柱成熟，部分恢复了Opcml−/−小鼠的异常行为。我们展示了精神分裂症易感基因OPCMLin通过调节ePhin-EphB2-cofilin信号通路在脊柱成熟和认知行为中的关键作用，为进一步了解精神分裂症的特征提供了进一步的见解。
Previous genetic and biological evidence converge on the involvement of synaptic dysfunction in schizophrenia, and OPCML, encoding a synaptic membrane protein, is reported to be genetically associated with schizophrenia. However, its role in the pathophysiology of schizophrenia remains largely unknown. Here, we found that Opcml is strongly expressed in the mouse hippocampus; ablation of Opcml leads to reduced phosphorylated cofilin and dysregulated F-actin dynamics, which disturbs the spine maturation. Furthermore, Opcml interacts with EphB2 to control the stability of spines by regulating the ephrin-EphB2-cofilin signaling pathway. Opcml-deficient mice display impaired cognitive behaviors and abnormal sensorimotor gating, which are similar to features in neuropsychiatric disorders such as schizophrenia. Notably, the administration of aripiprazole partially restores the abnormal behaviors inOpcml−/−mice by increasing the phosphorylated cofilin level and facilitating spine maturation. We demonstrated a critical role of the schizophrenia-susceptible geneOPCMLin spine maturation and cognitive behaviors via regulating the ephrin-EphB2-cofilin signaling pathway, providing further insights into the characteristics of schizophrenia.