Oligodendrocyte-derived LGI3 and its receptor ADAM23 organize juxtaparanodal Kv1 channel clustering for short-term synaptic plasticity.
Oligodendrocyte-derived LGI3 and its receptor ADAM23 organize juxtaparanodal Kv1 channel clustering for short-term synaptic plasticity.
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DOI：
10.1016/j.celrep.2023.113634
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发表时间：
2024-01-23
期刊：
影响因子：
8.8
通讯作者：
Fukata M
中科院分区：
文献类型：
--
作者：
Miyazaki Y;Otsuka T;Yamagata Y;Endo T;Sanbo M;Sano H;Kobayashi K;Inahashi H;Kornau HC;Schmitz D;Prüss H;Meijer D;Hirabayashi M;Fukata Y;Fukata M
神经发育障碍，如智力残疾（ID），癫痫和自闭症，涉及改变突触传递和可塑性。其相关基因的功能表征对于理解生理-病理脑功能至关重要。LGI 3是一个新近发现的ID相关基因，编码一种与癫痫基因产物LGI 1相关的分泌蛋白。在这里，我们发现，LGI 3是独特的分泌少突胶质细胞在大脑和丰富的有髓轴突的神经节，形成纳米级的亚簇。使用表位标记的Lgi 3敲入小鼠的蛋白质组学分析表明，LGI 3使用ADAM 23作为受体，并选择性地与Kv 1通道共组装。小鼠中缺乏Lgi 3会破坏ADAM 23和Kv 1通道的突触结簇，并抑制Kv 1通道介导的短期突触可塑性。总的来说，这项研究确定了一个细胞外的组织者的arctaparanodal Kv 1通道集群微调突触传递。鉴于LGI 3错义变体的分泌缺陷，我们提出了一种分子途径，即腹肢节LGI 3-ADAM 23-Kv 1通道，用于了解神经发育障碍。少突胶质细胞衍生的LGI 3在有髓轴突的近节区形成纳米簇LGI 3是ADAM 23和Kv 1通道的近节区聚集所必需的LGI 3调节大脑皮层中Kv 1通道依赖的短期可塑性近节区LGI 3-ADAM 23-Kv 1通道是ID宫崎et al.显示智力残疾相关配体LGI 3从少突胶质细胞分泌，并与其轴突受体ADAM 23一起特异性地聚集在有髓鞘轴突的神经节。LGI 3的特异性作用使我们能够偶然地分离出短期突触可塑性中普遍表达的Kv 1通道的亚细胞特异性作用。
Neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism, involve altered synaptic transmission and plasticity. Functional characterization of their associated genes is vital for understanding physio-pathological brain functions. LGI3 is a recently recognized ID-associated gene encoding a secretory protein related to an epilepsy-gene product, LGI1. Here, we find that LGI3 is uniquely secreted from oligodendrocytes in the brain and enriched at juxtaparanodes of myelinated axons, forming nanoscale subclusters. Proteomic analysis using epitope-tagged Lgi3 knockin mice shows that LGI3 uses ADAM23 as a receptor and selectively co-assembles with Kv1 channels. A lack of Lgi3 in mice disrupts juxtaparanodal clustering of ADAM23 and Kv1 channels and suppresses Kv1-channel-mediated short-term synaptic plasticity. Collectively, this study identifies an extracellular organizer of juxtaparanodal Kv1 channel clustering for finely tuned synaptic transmission. Given the defective secretion of the LGI3 missense variant, we propose a molecular pathway, the juxtaparanodal LGI3-ADAM23-Kv1 channel, for understanding neurodevelopmental disorders. Oligodendrocyte-derived LGI3 forms nanoclusters at juxtaparanodes of myelinated axons LGI3 is required for juxtaparanodal clustering of ADAM23 and Kv1 channels LGI3 regulates Kv1-channel-dependent short-term plasticity in the cerebral cortex Juxtaparanodal LGI3-ADAM23-Kv1 channel is a possible molecular pathway affected in ID Miyazaki et al. show that intellectual-disability-related ligand LGI3 is secreted from oligodendrocytes and specifically clustered at the juxtaparanode of myelinated axons together with its axonal receptor, ADAM23. The juxtaparanode-specific action of LGI3 allows us to serendipitously isolate a subcellular-specific role of ubiquitously expressed Kv1 channels in short-term synaptic plasticity.
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影响因子：
5.3
作者：
Crabtree, Gregg W.;Sun, Ziyi;Gogos, Joseph A.
通讯作者：
Gogos, Joseph A.
影响因子：
30.8
作者：
Kalachikov, S;Evgrafov, O;Gilliam, TC
通讯作者：
Gilliam, TC
DOI：
10.1073/pnas.2007965117
发表时间：
2020-10-27
影响因子：
11.1
作者：
Ejneby, Malin Silvera;Wallner, Bjorn;Elinder, Fredrik
通讯作者：
Elinder, Fredrik
影响因子：
4.5
作者：
Seppälä EH;Jokinen TS;Fukata M;Fukata Y;Webster MT;Karlsson EK;Kilpinen SK;Steffen F;Dietschi E;Leeb T;Eklund R;Zhao X;Rilstone JJ;Lindblad-Toh K;Minassian BA;Lohi H
通讯作者：
Lohi H
DOI：
10.1093/brain/awq213
发表时间：
2010-09
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Irani SR;Alexander S;Waters P;Kleopa KA;Pettingill P;Zuliani L;Peles E;Buckley C;Lang B;Vincent A
通讯作者：
Vincent A