A CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance.
A CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance.
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DOI：
10.1038/ncomms10090
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发表时间：
2015-12-10
影响因子：
16.6
通讯作者：
Kinoshita M
中科院分区：
文献类型：
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作者：
Ageta-Ishihara N;Yamazaki M;Konno K;Nakayama H;Abe M;Hashimoto K;Nishioka T;Kaibuchi K;Hattori S;Miyakawa T;Tanaka K;Huda F;Hirai H;Hashimoto K;Watanabe M;Sakimura K;Kinoshita M
gtpase小效应蛋白CDC42EP1-5/ BORG1-5与CDC42或septin细胞骨架相互作用。本研究表明，在小脑中，CDC42EP4仅在伯格曼胶质细胞中表达，并定位于包裹浦肯野细胞树突棘的特定膜域下。CDC42EP4与septin异聚物形成复合物，与谷氨酸转运体GLAST/EAAT1亚群相互作用。在Cdc42ep4 - / -小鼠中，GLAST从septin中分离出来，并在远离平行纤维-浦肯野细胞突触的地方离域。兴奋性突触后电流表现出延长的衰减时间常数，对ampa型谷氨酸受体竞争性抑制剂（γ - dgg）的敏感性降低，以及对谷氨酸转运蛋白/ EAAT1-5 （DL-TBOA）的非选择性抑制剂的亚阈值剂量反应时基线内向电流过高。这些小鼠的谷氨酸缓冲/清除能力不足表现为运动协调/学习缺陷，阈下DL-TBOA加重了这种缺陷。我们认为基于CDC42EP4/septin的胶质支架促进了谷氨酸last的突触周围定位，并优化了谷氨酸缓冲和清除的效率。谷氨酸转运体介导谷氨酸能突触的神经递质再摄取。在这里，作者表明CDC42效应蛋白CDC42EP4通过促进谷氨酸转运体GLAST粘附到伯格曼胶质细胞的突触周围簇来支持谷氨酸的有效清除。
The small GTPase-effector proteins CDC42EP1-5/BORG1–5 interact reciprocally with CDC42 or the septin cytoskeleton. Here we show that, in the cerebellum, CDC42EP4 is exclusively expressed in Bergmann glia and localizes beneath specific membrane domains enwrapping dendritic spines of Purkinje cells. CDC42EP4 forms complexes with septin hetero-oligomers, which interact with a subset of glutamate transporter GLAST/EAAT1. In Cdc42ep4−/− mice, GLAST is dissociated from septins and is delocalized away from the parallel fibre-Purkinje cell synapses. The excitatory postsynaptic current exhibits a protracted decay time constant, reduced sensitivity to a competitive inhibitor of the AMPA-type glutamate receptors (γDGG) and excessive baseline inward current in response to a subthreshold dose of a nonselective inhibitor of the glutamate transporters/EAAT1–5 (DL-TBOA). Insufficient glutamate-buffering/clearance capacity in these mice manifests as motor coordination/learning defects, which are aggravated with subthreshold DL-TBOA. We propose that the CDC42EP4/septin-based glial scaffold facilitates perisynaptic localization of GLAST and optimizes the efficiency of glutamate-buffering and clearance. Glutamate transporters mediate neurotransmitter reuptake at glutamatergic synapses. Here the authors show that CDC42 effector protein CDC42EP4 supports efficient glutamate clearance by promoting the tethering of a glutamate transporter GLAST to perisynaptic clusters of septins in Bergmann glia.