Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, Via Celoria 11,20133 Milan, Italy.
Neuroscience. 2011 Feb 23;175:380-93. doi: 10.1016/j.neuroscience.2010.11.061. Epub 2010 Dec 3.
Cortical dysplasia (CD) comprises a wide range of cerebral cortex alterations ranging from severe brain malformations to local disruption of the cortical structure. Most hypotheses focused on the role of embryonic/perinatal development insults as the main cause for the majority of CD. Rats with prenatal exposure to BCNU (1-3-bis-chloroethyl-nitrosurea) represent an injury-based model and reproduce many anatomical features seen in human patients with CD, such as altered cortical layering and the presence of heterotopia and dysmorphic/heterotopic neurons. With the aim to investigate the formation and evolution of CD during development, we analysed the expression of a panel of layer-specific genes (Nurr1, Er81, Ror-β and Cux2, markers of layers VI, V, IV and superficial layers, respectively) in BCNU-treated cortices from E17 to postnatal day 14. By means of appropriate immunohistochemical markers, we also analysed the structural organization of embryonic ventricular zone and of glial and axonal fibres, substrates supporting radial and tangential migration, respectively. The main results of the present study are: (i) the ventricular zone appeared disorganized and the neuroependyma was partially disrupted; (ii) radial glia scaffold and tangential fibres were deeply disarranged, thus explaining the neuronal migration defects; (iii) cortical heterotopia were detectable by E19, whereas periventricular heterotopia were detectable after birth; (iv) both cortical and periventricular heterotopia showed a pseudo-laminar structure, with cells of the upper cortical layers in the core of the nodules and cells of layer IV and V at their border; (v) the distribution of GABAergic cells was altered since the embryonic stages, as a consequence of the derangement of tangential fibres. Our analysis sheds light on how a malformed cortex develops after a temporally discrete environmental insult and adds additional knowledge on specific aspects of the etiopathogenesis of CD.
皮质发育不良（CD）是一种广泛的大脑皮层改变，从严重的脑畸形到皮质结构的局部破坏。大多数假说都集中在胚胎/围产期发育损伤作为大多数 CD 的主要原因。在产前暴露于 BCNU（1-3-双氯乙基-亚硝脲）的大鼠代表了一种基于损伤的模型，它再现了许多在 CD 患者中看到的解剖特征，例如皮层分层改变、异位和畸形/异位神经元存在。为了研究 CD 在发育过程中的形成和演变，我们分析了 E17 至出生后 14 天的 BCNU 处理皮质中一组层特异性基因（Nurr1、Er81、Ror-β 和 Cux2，分别为 VI、V、IV 和浅层的标志物）的表达。通过适当的免疫组织化学标志物，我们还分析了胚胎室管膜区以及支持放射状和切线迁移的神经胶质和轴突纤维的结构组织。本研究的主要结果是：（i）室管膜区显得紊乱，神经上皮部分破坏；（ii）放射状胶质支架和切线纤维严重混乱，从而解释了神经元迁移缺陷；（iii）E19 时可检测到皮质异位，而出生后可检测到脑室周围异位；（iv）皮质和脑室周围异位均表现出假层状结构，结节核心处有上层皮质细胞，边缘处有 IV 和 V 层细胞；（v）由于切线纤维的紊乱，胚胎期后 GABA 能细胞的分布发生改变。我们的分析揭示了在短暂的环境损伤后畸形皮层是如何发育的，并为 CD 的发病机制的特定方面增加了额外的知识。
