Jiang Yulan, Gavrilovici Cezar, Chansard Mathieu, Liu Rui Han, Kiroski Ivana, Parsons Kari, Park Sang Ki, Teskey G Campbell, Rho Jong M, Nguyen Minh Dang
Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Alberta Children Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Departments of Pediatrics and Clinical Neurosciences, Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
J Neurosci. 2016 Jun 15;36(24):6538-52. doi: 10.1523/JNEUROSCI.2869-15.2016.
How the integrity of laminar structures in the postnatal brain is maintained impacts neuronal functions. Ndel1, the mammalian homolog of NuDE from the filamentous fungus Aspergillus nidulans, is an atypical microtubule (MT)-associated protein that was initially investigated in the contexts of neurogenesis and neuronal migration. Constitutive knock-out mice for Ndel1 are embryonic lethal, thereby necessitating the creation a conditional knock-out to probe the roles of Ndel1 in postnatal brains. Here we report that CA1 pyramidal neurons from mice postnatally lacking Ndel1 (Ndel1 conditional knock-out) exhibit fragmented MTs, dendritic/synaptic pathologies, are intrinsically hyperexcitable and undergo dispersion independently of neuronal migration defect. Secondary to the pyramidal cell changes is the decreased inhibitory drive onto pyramidal cells from interneurons. Levels of the glycoprotein Reelin that regulates MTs, neuronal plasticity, and cell compaction are significantly reduced in hippocampus of mutant mice. Strikingly, a single injection of Reelin into the hippocampus of Ndel1 conditional knock-out mice ameliorates ultrastructural, cellular, morphological, and anatomical CA1 defects. Thus, Ndel1 and Reelin contribute to maintain postnatal CA1 integrity.
The significance of this study rests in the elucidation of a role for Nde1l and Reelin in postnatal CA1 integrity using a new conditional knock-out mouse model for the cytoskeletal protein Ndel1, one that circumvents the defects associated with neuronal migration and embryonic lethality. Our study serves as a basis for understanding the mechanisms underlying postnatal hippocampal maintenance and function, and the significance of decreased levels of Ndel1 and Reelin observed in patients with neurological disorders.
出生后大脑中层状结构的完整性如何维持会影响神经元功能。Ndel1是丝状真菌构巢曲霉中NuDE的哺乳动物同源物，是一种非典型的微管（MT）相关蛋白，最初是在神经发生和神经元迁移的背景下进行研究的。Ndel1的组成型敲除小鼠在胚胎期致死，因此需要创建条件性敲除来探究Ndel1在出生后大脑中的作用。在此我们报告，出生后缺乏Ndel1的小鼠（Ndel1条件性敲除）的CA1锥体神经元表现出微管断裂、树突/突触病变，内在兴奋性过高，并且在不依赖神经元迁移缺陷的情况下发生分散。锥体细胞变化的继发结果是来自中间神经元对锥体细胞的抑制驱动减弱。调节微管、神经元可塑性和细胞紧实度的糖蛋白Reelin水平在突变小鼠的海马体中显著降低。令人惊讶的是，向Ndel1条件性敲除小鼠的海马体单次注射Reelin可改善超微结构、细胞、形态和解剖学上的CA1缺陷。因此，Ndel1和Reelin有助于维持出生后CA1的完整性。
本研究的意义在于，使用一种针对细胞骨架蛋白Ndel1的新的条件性敲除小鼠模型，阐明Nde1l和Reelin在出生后CA1完整性中的作用，该模型规避了与神经元迁移和胚胎致死相关的缺陷。我们的研究为理解出生后海马体维持和功能的潜在机制，以及在神经疾病患者中观察到的Ndel1和Reelin水平降低的意义提供了基础。
