Inhibition of N-methyl-d-aspartate receptor activity resulted in aberrant neuronal migration caused by delayed morphological development in the mouse neocortex
Inhibition of N-methyl-d-aspartate receptor activity resulted in aberrant neuronal migration caused by delayed morphological development in the mouse neocortex
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DOI：
10.1016/j.neuroscience.2010.05.024
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发表时间：
2010-08
期刊：
影响因子：
3.3
通讯作者：
S. Uchino;T. Hirasawa;H. Tabata;Y. Gonda;C. Waga;Y. Ondo;K. Nakajima;S. Kohsaka
中科院分区：
文献类型：
--
作者：
S. Uchino;T. Hirasawa;H. Tabata;Y. Gonda;C. Waga;Y. Ondo;K. Nakajima;S. Kohsaka
胚胎和新生儿的新皮质神经元在形成突触之前已经表达了功能性n -甲基-d-天冬氨酸（NMDA）受体。为了阐明NMDA受体在发育中的新皮层神经元迁移中的作用，我们在E15.5时使用子宫电穿孔将增强的绿色荧光蛋白（EGFP）基因转移到小鼠新皮层的心室区（VZ），以观察径向迁移的神经元。两天后，我们准备了新皮质切片，并在NMDA受体拮抗剂Cerestat的存在下使用延时成像检查egfp阳性细胞。在对照切片中，在VZ区生成的egfp阳性细胞呈现多极形态，但在几小时内它们变成双极（具有前导过程和轴突样过程）并向脑脊液表面迁移。相比之下，cerestat处理的切片中的许多多极细胞未能扩展任何一个过程而变成双极，并且经常改变方向，尽管即使在cerestat处理后它们最终到达目的地。为了确定在神经元迁移过程中介导NMDA信号传导的分子以及上述观察到的形态学变化，我们在这里重点研究了Src家族激酶（SFKs），它介导了包括迁移和神经突延伸在内的多种神经元功能。我们发现Cerestat降低了Src和Fyn的活性。这些发现表明，NMDA受体参与了神经元的迁移和两极形态的改变，并参与了发育中的新皮层中Src和Fyn的激活。
Embryonic and neonatal neocortical neurons already express functional N-methyl-d-aspartate (NMDA) receptors before they form synapses. To elucidate the role of NMDA receptors in neuronal migration in the developing neocortex, we visualized radially migrating neurons by transferring the enhanced green fluorescent protein (EGFP) gene into the ventricular zone (VZ) of the mouse neocortex using in utero electroporation at E15.5. Two days later, we prepared neocortical slices and examined the EGFP-positive cells using time-lapse imaging in the presence of the NMDA receptor antagonist Cerestat. The EGFP-positive cells generated in the VZ in the control slices exhibited a multipolar morphology, but within several hours they became bipolar (with a leading process and an axon-like process) and migrated toward the pial surface. By contrast, many of the multipolar cells in the Cerestat-treated slices failed to extend either process and become bipolar, and frequently changed direction, although they ultimately reached their destination even after Cerestat-treatment. To identify the molecules responding for mediating NMDA signaling during neuronal migration and the changes in morphology observed above, we here focused on Src family kinases (SFKs), which mediate a variety of neuronal functions including migration and neurite extension. We discovered that the activity of Src and Fyn was reduced by Cerestat. These findings suggest that NMDA receptors are involved in neuronal migration and morphological changes into a bipolar shape, and in the activation of Src and Fyn in the developing neocortex.