Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan.
Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan.
J Neurochem. 2018 Nov;147(3):344-360. doi: 10.1111/jnc.14486. Epub 2018 Aug 8.
Mlc1 is a causative gene for megalencephalic leukoencephalopathy with subcortical cysts, and is expressed in astrocytes. Mlc1-over-expressing mice represent an animal model of early-onset leukoencephalopathy, which manifests as astrocytic swelling followed by myelin membrane splitting in the white matter. It has been previously reported that Mlc1 is highly expressed in Bergmann glia, while the cerebellar phenotypes of Mlc1-over-expressing mouse have not been characterized. Here, we examined the cerebellum of Mlc1-over-expressing mouse and found that the distribution of Bergmann glia (BG) was normally compacted along the Purkinje cell (PC) layer until postnatal day 10 (P10), while most BG were dispersed throughout the molecular layer by P28. Ectopic BG were poorly wrapped around somatodendritic elements of PCs and exhibited reduced expression of the glutamate transporter glutamate-aspartate transporter. Extraordinarily slow and small climbing fiber (CF)-mediated excitatory post-synaptic currents, which are known to be elicited under accelerated glutamate spillover, emerged at P20-P28 when BG ectopia was severe, but not at P9-P12 when ectopia was mild. Furthermore, maturation of CF wiring, which translocates the site of innervation from somata to proximal dendrites, was also impaired. Manipulations that restricted the Mlc1-over-expressing period successfully generated mice with and without BG ectopia, depending on the over-expressing period. Together, these findings suggest that there is a critical time window for mechanisms that promote the positioning of BG in the PC layer. Once normal positioning of BG is affected, the differentiation of BG is impaired, leading to insufficient glial wrapping, exacerbated glutamate spillover, and aberrant synaptic wiring in PCs. Open Practices Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ Cover Image for this issue: doi: 10.1111/jnc.14199.
Mlc1 是巨脑性脑白质营养不良伴皮质下囊肿的致病基因，在星形胶质细胞中表达。Mlc1 过表达小鼠代表一种早发性脑白质病的动物模型，其表现为星形胶质细胞肿胀，随后白质中的髓鞘膜分裂。此前有报道称，Mlc1 在 Bergmann 胶质细胞中高度表达，而 Mlc1 过表达小鼠的小脑表型尚未得到表征。在这里，我们检查了 Mlc1 过表达小鼠的小脑，发现 Bergmann 胶质细胞（BG）的分布在出生后第 10 天（P10）之前正常地沿着浦肯野细胞（PC）层紧密排列，而到 P28 时，大多数 BG 则散布在分子层中。异位 BG 很少围绕 PC 的体树突元件包裹，谷氨酸转运体谷氨酸-天冬氨酸转运体的表达减少。在 BG 异位严重的 P20-P28 时，出现了异常缓慢和小的 climbing fiber（CF）介导的兴奋性突触后电流，已知在谷氨酸溢出加速时会引发这种电流，而在 P9-P12 时异位较轻时则不会出现这种电流。此外，CF 布线的成熟也受到了损害，CF 布线会将神经支配的部位从胞体转移到近端树突。限制 Mlc1 过表达周期的操作成功地产生了具有和不具有 BG 异位的小鼠，这取决于过表达周期。综上所述，这些发现表明存在促进 BG 在 PC 层中定位的机制的关键时间窗口。一旦 BG 的正常定位受到影响，BG 的分化就会受损，导致胶质包裹不足、谷氨酸溢出加剧以及 PC 中的异常突触连接。开放实践：开放科学：本文获得了开放材料徽章。有关更多信息，请参见：https://cos.io/our-services/open-science-badges/本期封面图片：doi：10.1111/jnc.14199.
