Nogo-A Stabilizes the Architecture of Hippocampal Neurons
Nogo-A Stabilizes the Architecture of Hippocampal Neurons
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DOI：
10.1523/jneurosci.1044-10.2010
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发表时间：
2010-10-06
影响因子：
5.3
通讯作者：
Korte, Martin
中科院分区：
文献类型：
--
作者：
Zagrebelsky, Marta;Schweigreiter, Ruediger;Korte, Martin
虽然髓磷脂衍生的Nogo-A作为CNS损伤后轴突再生的抑制剂的作用已被充分描述，但其在成年未损伤CNS中的生理功能鲜为人知。我们在海马中解决这个问题，其中Nogo-A由神经元和少突胶质细胞表达。我们使用了21天的新生儿海马体外切片培养物，其中我们采用不同的方法来干扰Nogo-A信号传导和表达，并分析其对锥体细胞树突和轴突结构的影响。通过功能阻断抗体中和Nogo-A引起海马锥体神经元树突结构的重大改变。尽管棘密度不受Nogo-A中和的影响，但棘类型分布向更不成熟的表型转移。轴突的复杂性和长度大大增加。Nogo-A KO小鼠显示出类似于抗体治疗效果的弱树突状表型。为了区分Nogo-A可能的细胞自主作用与环境受体介导的功能，我们研究了短发夹RNA诱导的Nogo-A或NgR 1（一种突出的Nogo-A受体）在单个神经元内敲低的影响。敲除Nogo-A复制了树突的一部分，而没有脊柱或轴突的改变。然而，NgR 1的下调复制了Nogo-A中和后观察到的树突、轴突和棘的改变。总之，我们的研究结果表明，Nogo-A在稳定和维持海马锥体神经元的结构中起着重要作用。从机制上讲，尽管Nogo-A的大部分活性依赖于涉及NgR 1的受体介导的机制，但其细胞自主功能起次要作用。
Although the role of myelin-derived Nogo-A as an inhibitor of axonal regeneration after CNS injury has been thoroughly described, its physiological function in the adult, uninjured CNS is less well known. We address this question in the hippocampus, where Nogo-A is expressed by neurons as well as oligodendrocytes. We used 21 d in vitro slice cultures of neonatal hippocampus where we applied different approaches to interfere with Nogo-A signaling and expression and analyze their effects on the dendritic and axonal architecture of pyramidal cells. Neutralization of Nogo-A by function-blocking antibodies induced a major alteration in the dendrite structure of hippocampal pyramidal neurons. Although spine density was not influenced by Nogo-A neutralization, spine type distribution was shifted toward a more immature phenotype. Axonal complexity and length were greatly increased. Nogo-A KO mice revealed a weak dendritic phenotype resembling the effect of the antibody treatment. To discriminate a possible cell-autonomous role of Nogo-A from an environmental, receptor-mediated function, we studied the effects of short hairpin RNA-induced knockdown of Nogo-A or NgR1, a prominent Nogo-A receptor, within individual neurons. Knockdown of Nogo-A reproduced part of the dendritic and none of the spine or axon alterations. However, downregulation of NgR1 replicated the dendritic, the axonal, and the spine alterations observed after Nogo-A neutralization. Together, our results demonstrate that Nogo-A plays a major role in stabilizing and maintaining the architecture of hippocampal pyramidal neurons. Mechanistically, although the majority of the activity of Nogo-A relies on a receptor-mediated mechanism involving NgR1, its cell-autonomous function plays a minor role.