Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
Hippocampus. 2011 Sep;21(9):935-44. doi: 10.1002/hipo.20793. Epub 2010 May 17.
Cajal-Retzius cells play a crucial role during ontogeny in regulating cortical lamination via release of reelin. In adult brain, they comprise small calretinin-positive interneurons located in the marginal zone of the cerebral cortex and in the hippocampal fissure. Alterations of reelin signaling or expression have been involved in major neurological disorders, and they underlie granule cell dispersion (GCD) in mesial temporal lobe epilepsy (TLE). Here, we investigated in a mouse model of TLE the contribution of Cajal-Retzius cells to reelin production in epileptic hippocampus and the molecular mechanisms underlying GCD. Following unilateral intrahippocampal Kainic acid injection in adult mice to induce an epileptic focus, we observed that Cajal-Retzius cells gradually became strongly immunopositive for reelin, due to intracellular accumulation. This phenotype resembled the morphology of Cajal-Retzius cells in reeler Orleans (reln (orl/orl) ) mice, which express a secretion-deficient 310-kDa reelin fragment. The possibility that GCD might result from abnormal reelin processing in Cajal-Retzius cells, leading to a lack of reelin secretion, was confirmed by KA injection in reln (orl/+) mice, which induced severe GCD. Furthermore, Western blot analysis in KA-treated wildtype mice revealed increased production of ∼300-kDa reelin fragments, confirming abnormal proteolytic processing. This effect was not seen upon treatment with Botulinum neurotoxin E (BoNT/E), which prevents GCD in KA-lesioned hippocampus by chronic blockade of synaptic transmission. Furthermore, BoNT/E blocked upregulation of TrkB in Cajal-Retzius cells, suggesting that production of truncated reelin in KA-treated hippocampus is activity-dependent and regulated by BDNF. Altogether, these data reveal that GCD results from abnormal reelin processing in Cajal-Retzius cells under the control of BDNF. Our findings highlight the critical role played by Cajal-Retzius cells for hippocampal neuronal reorganization in TLE.
Cajal-Retzius 细胞通过释放 reelin 在皮层分层中发挥关键作用。在成年大脑中，它们是位于大脑皮层边缘区和海马裂中的小 calretinin 阳性中间神经元。reelin 信号或表达的改变与主要神经障碍有关，并在颞叶内侧癫痫（TLE）的颗粒细胞分散（GCD）中起基础作用。在这里，我们在 TLE 的小鼠模型中研究了 Cajal-Retzius 细胞对癫痫海马 reelin 产生的贡献以及 GCD 的分子机制。在成年小鼠单侧海马内注射 Kainic 酸以诱导癫痫灶后，我们观察到 Cajal-Retzius 细胞由于细胞内积累而逐渐对 reelin 呈强烈免疫阳性。这种表型类似于 Orleans 型 reeler（reln（orl/orl））小鼠中 Cajal-Retzius 细胞的形态，其表达一种缺乏分泌功能的 310-kDa reelin 片段。KA 注射到 reln（orl/+）小鼠中会诱导严重的 GCD，证实了 GCD 可能是由于 Cajal-Retzius 细胞中异常的 reelin 加工导致缺乏 reelin 分泌所致。此外，在 KA 处理的野生型小鼠中进行的 Western blot 分析显示，产生了增加的∼300-kDa reelin 片段，证实了异常的蛋白水解加工。在用 Botulinum neurotoxin E（BoNT/E）处理时不会出现这种效应，BoNT/E 通过慢性阻断突触传递来防止 KA 损伤海马中的 GCD。此外，BoNT/E 阻断了 Cajal-Retzius 细胞中 TrkB 的上调，表明 KA 处理的海马中截断的 reelin 的产生是活性依赖性的，并受 BDNF 调节。总之，这些数据表明，GCD 是由 BDNF 控制下 Cajal-Retzius 细胞中异常的 reelin 加工引起的。我们的研究结果揭示了 Cajal-Retzius 细胞在 TLE 中海马神经元重组中所起的关键作用。
