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CDC42EP4, a perisynaptic scaffold protein in Bergmann glia, is required for glutamatergic tripartite synapse configuration
Neurochemistry international ( IF 4.2 ) Pub Date : 2018-01-09 , DOI: 10.1016/j.neuint.2018.01.003
Natsumi Ageta-Ishihara , Kohtarou Konno , Maya Yamazaki , Manabu Abe , Kenji Sakimura , Masahiko Watanabe , Makoto Kinoshita

Configuration of tripartite synapses, comprising the pre-, post-, and peri-synaptic components (axon terminal or bouton, dendritic spine, and astroglial terminal process), is a critical determinant of neurotransmitter kinetics and hence synaptic transmission. However, little is known about molecular basis for the regulation of tripartite synapse morphology. Previous studies showed that CDC42EP4, an effector protein of a cell morphogenesis regulator CDC42, is expressed exclusively in Bergmann glia in the cerebellar cortex, that it forms tight complex with the septin heterooligomer, and that it interacts indirectly with the glutamate transporter GLAST and MYH10/nonmuscle myosin ΙΙB. Scrutiny of Cdc42ep4−/− mice had revealed that the CDC42EP4-septins-GLAST interaction facilitates glutamate clearance, while the role for CDC42EP4-septins-MYH10 interaction has remained unsolved. Here, we find anomalous configuration of the tripartite synapses comprising the parallel fiber boutons, dendritic spines of Purkinje cells, and Bergmann glial processes in Cdc42ep4−/− mice. The complex anomalies include 1) recession of Bergmann glial membranes from the nearest active zones, and 2) extension of nonactive synaptic contact around active zone. In line with the recession of Bergmann glial membranes by the loss of CDC42EP4, overexpression of CDC42EP4 in heterologous cells promotes cell spreading and partitioning of MYH10 to insoluble (i.e., active) fraction. Paradoxically, however, Cdc42ep4−/− cerebellum contained significantly more MYH10 and N-cadherin, which is attributed to secondary neuronal response mainly in Purkinje cells. Given cooperative actions of N-cadherin and MYH10 for adhesion between neurons, we speculate that their augmentation may reflect the extension of nonactive synaptic contacts in Cdc42ep4−/− cerebellum. Transcellular mechanism that links the absence of CDC42EP4 in Bergmann glia to the augmentation of N-cadherin and MYH10 in neurons is currently unknown, but the phenotypic similarity to GLAST-null mice indicates involvement of the glutamate intolerance. Together, the unique phenotype of Cdc42ep4−/− mice provides a clue to novel molecular network underlying tripartite synapse configuration.



中文翻译:

CDC42EP4是Bergmann神经胶质中的突触周围支架蛋白,是谷氨酸能三联突触构型所必需的

包括突触前,突触后和突触周围成分(轴突末端或钮扣,树突状脊柱和星形胶质终末过程)的三重突触的构型是神经递质动力学和突触传递的关键决定因素。然而,关于三方突触形态调节的分子基础知之甚少。先前的研究表明,CDC42EP4是一种细胞形态发生调节因子CDC42的效应蛋白,仅在小脑皮层的Bergmann胶质细胞中表达,它与septin杂聚物形成紧密的复合物,并与谷氨酸转运蛋白GLAST和MYH10 /间接相互作用。非肌肉肌球蛋白IIB。审查Cdc42ep4 -/-小鼠已经揭示了CDC42EP4-septins-GLAST相互作用促进了谷氨酸清除,而CDC42EP4-septins-MYH10相互作用的作用尚未解决。在这里,我们发现Cdc42ep4 -/-小鼠中由平行纤维纽扣,浦肯野细胞的树突棘和Bergmann胶质突形成的三联突触的异常构型。复杂的异常现象包括:1)Bergmann神经胶质膜从最近的活动区后退;以及2)围绕活动区的非活动突触接触的扩展。与CDC42EP4的丧失导致Bergmann胶质细胞膜退缩相一致,异源细胞中CDC42EP4的过表达促进细胞扩散和将MYH10分配为不溶(活性)部分。然而,自相矛盾的是Cdc42ep4 -/-小脑包含明显更多的MYH10和N-钙粘着蛋白,这归因于主要在浦肯野细胞中的继发性神经元反应。考虑到N-钙粘着蛋白和MYH10对神经元之间粘附的协同作用,我们推测它们的增加可能反映了Cdc42ep4 -/-小脑中非活性突触接触的扩展。目前尚不知道将Bergmann胶质细胞CDC42EP4的缺乏与神经元N-钙粘蛋白和MYH10的增加联系起来的跨细胞机制,但与GLAST-null小鼠的表型相似性表明涉及谷氨酸不耐受。在一起,Cdc42ep4的独特表型-/- 小鼠为潜在的三方突触构型的新型分子网络提供了线索。

更新日期:2018-01-09
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