Ectopic positioning of Bergmann glia and impaired cerebellar wiring in Mlc1‐over‐expressing mice. Issue 3 (8th August 2018)

• Record Type: Journal Article
• Authors: Kikuchihara, Saori; Sugio, Shouta; Tanaka, Kenji F.; Watanabe, Takaki; Kano, Masanobu; Yamazaki, Yoshihiko; Watanabe, Masahiko; Ikenaka, Kazuhiro
• Is Part Of: Journal of neurochemistry. Volume 147:Issue 3(2018)
• Page Start: 344
• Page End: 360
• Publication Date: 2018-08-08
• Subjects: Bergmann glia -- climbing fiber -- Mlc1 -- Purkinje cell; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14486
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: 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 . Abstract : Mlc1 is a causative gene for megalencephalic leukoencephalopathy with subcortical cysts. In the cerebellum, Mlc1 is highly expressed in Bergmann glia (BG), which is one of the astrocyte associated with Purkinje cells (PCs). Here, we found that Mlc1 over‐expression in astrocyte resulted in the BG ectopia and insufficient association with PCs, and we revealed the critical time window inducing BG ectopia. Once BG impairments were established, synaptic wiring on PCs were affected by glutamate spillover via the insufficient BG association. Our results indicated that time course of BG cytodifferentiation is one of the crucial determinant for synaptic wiring on PCs. Cover Image for this issue: doi:10.1111/jnc.14199 .