Belichenko Pavel V, Wright Elena E, Belichenko Nadia P, Masliah Eliezer, Li Hong Hua, Mobley William C, Francke Uta
Neuroscience Institute at Stanford University, Stanford, CA 94305-5489, USA.
J Comp Neurol. 2009 May 20;514(3):240-58. doi: 10.1002/cne.22009.
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked gene MECP2. Girls with RTT show dramatic changes in brain function, but relatively few studies have explored the structure of neural circuits. Examining two mouse models of RTT (Mecp2B and Mecp2J), we previously documented changes in brain anatomy. Herein, we use confocal microscopy to study the effects of MeCP2 deficiency on the morphology of dendrites and axons in the fascia dentata (FD), CA1 area of hippocampus, and motor cortex following Lucifer yellow microinjection or carbocyanine dye tracing. At 3 weeks of age, most (33 of 41) morphological parameters were significantly altered in Mecp2B mice; fewer (23 of 39) were abnormal in Mecp2J mice. There were striking changes in the density and size of the dendritic spines and density and orientation of axons. In Mecp2B mice, dendritic spine density was decreased in the FD (approximately 11%), CA1 (14-22%), and motor cortex (approximately 16%). A decreased spine head size (approximately 9%) and an increased spine neck length (approximately 12%) were found in Mecp2B FD. In addition, axons in the motor cortex were disorganized. In Mecp2J mice, spine density was significantly decreased in CA1 (14-26%). In both models, dendritic swelling and elongated spine necks were seen in all areas studied. Marked variation in the type and extent of changes was noted in dendrites of adjacent neurons. Electron microscopy confirmed abnormalities in dendrites and axons and showed abnormal mitochondria. Our findings document widespread abnormalities of dendrites and axons that recapitulate those seen in RTT.
雷特综合征（RTT）是一种由X连锁基因MECP2突变引起的神经发育障碍。患有RTT的女孩大脑功能会发生显著变化，但相对较少的研究探索了神经回路的结构。通过研究两种RTT小鼠模型（Mecp2B和Mecp2J），我们之前记录了大脑解剖结构的变化。在此，我们使用共聚焦显微镜，通过荧光黄显微注射或花青染料示踪，研究MeCP2缺乏对齿状回（FD）、海马CA1区和运动皮层中树突和轴突形态的影响。在3周龄时，Mecp2B小鼠中大多数（41个中的33个）形态学参数发生了显著改变；Mecp2J小鼠中异常的参数较少（39个中的23个）。树突棘的密度和大小以及轴突的密度和方向都有显著变化。在Mecp2B小鼠中，FD（约11%）、CA1（14 - 22%）和运动皮层（约16%）的树突棘密度降低。在Mecp2B的FD中发现棘头大小减小（约9%）和棘颈长度增加（约12%）。此外，运动皮层中的轴突排列紊乱。在Mecp2J小鼠中，CA1区的棘密度显著降低（14 - 26%）。在两种模型中，在所研究的所有区域都观察到树突肿胀和棘颈延长。相邻神经元的树突在变化类型和程度上存在明显差异。电子显微镜证实了树突和轴突的异常，并显示出线粒体异常。我们的研究结果记录了树突和轴突广泛存在的异常，这些异常与RTT中所见的异常情况相似。
