Loss of Nogo-A, encoded by the schizophrenia risk gene Rtn4, reduces mGlu3 expression and causes hyperexcitability in hippocampal CA3 circuits.
Loss of Nogo-A, encoded by the schizophrenia risk gene Rtn4, reduces mGlu3 expression and causes hyperexcitability in hippocampal CA3 circuits.
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DOI：
10.1371/journal.pone.0200896
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Ster J
中科院分区：
文献类型：
--
作者：
Berry S;Weinmann O;Fritz AK;Rust R;Wolfer D;Schwab ME;Gerber U;Ster J
最近对Nogo-A的研究发现，Nogo-A具有额外的功能，包括在精神分裂症等神经精神障碍中的作用。Nogo-A是一种具有良好特征的大脑中突起生长的蛋白质抑制剂。在这里，我们研究了Nogo-A在小鼠CA3海马区电路中的功能。膜片钳记录显示，Nogo-A的缺失导致了网络的过度活跃。此外，在某些类型的精神分裂症中表现出突变的mGlu3代谢性谷氨酸受体，在CA3区特异性下调。此外，Nogo-A-/-小鼠表现出与mGlu3-/-小鼠相似的紊乱的theta振荡，发生率和频率都降低了。由于theta节律性的紊乱与空间导航受损有关，我们使用改进的Morris水迷宫任务对小鼠进行了测试。缺乏Nogo-A的小鼠表现出搜索策略的改变，表现出对全局参照系的更大依赖，而不是局部参照系。Nogo-A和mGlu3受体之间的这种联系可能为精神分裂症的发病机制提供新的见解。
Recent investigations of Nogo-A, a well characterized protein inhibitor of neurite outgrowth in the brain, have revealed additional functions including a role in neuropsychiatric disorders such as schizophrenia. Here we examined Nogo-A functions in mouse CA3 hippocampal circuitry. Patch clamp recordings showed that the absence of Nogo-A results in a hyperactive network. In addition, mGlu3 metabotropic glutamate receptors, which exhibit mutations in certain forms of schizophrenia, were downregulated specifically in the CA3 area. Furthermore, Nogo-A-/- mice showed disordered theta oscillations with decreased incidence and frequency, similar to those observed in mGlu3-/- mice. As disruptions in theta rhythmicity are associated with impaired spatial navigation, we tested mice using modified Morris water maze tasks. Mice lacking Nogo-A exhibited altered search strategies, displaying greater dependence on global as opposed to local reference frames. This link between Nogo-A and mGlu3 receptors may provide new insights into mechanisms underlying schizophrenia.
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