气候变化领域集成服务门户(CCPortal): Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response

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DOI	10.1073/pnas.2022921118
	Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response
	Sun D.; Tan Z.-B.; Sun X.-D.; Liu Z.-P.; Chen W.-B.; Milibari L.; Ren X.; Yao L.-L.; Lee D.; Shen C.; Pan J.-X.; Huang Z.-H.; Mei L.; Xiong W.-C.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	Epilepsy, a common neurological disorder, is featured with recurrent seizures. Its underlying pathological mechanisms remain elusive. Here, we provide evidence for loss of neogenin (NEO1), a coreceptor for multiple ligands, including netrins and bone morphological proteins, in the development of epilepsy. NEO1 is reduced in hippocampi from patients with epilepsy based on transcriptome and proteomic analyses. Neo1 knocking out (KO) in mouse brains displays elevated epileptiform spikes and seizure susceptibility. These phenotypes were undetectable in mice, with selectively depleted NEO1 in excitatory (NeuroD6-Cre+) or inhibitory (parvalbumin+) neurons, but present in mice with specific hippocampal astrocytic Neo1 KO. Additionally, neurons in hippocampal dentate gyrus, a vulnerable region in epilepsy, in mice with astrocyte-specific Neo1 KO show reductions in inhibitory synaptic vesicles and the frequency of miniature inhibitory postsynaptic current(mIPSC), but increase of the duration of miniature excitatory postsynaptic current and tonic NMDA receptor currents, suggesting impairments in both GABAergic transmission and extracellular glutamate clearance. Further proteomic and cell biological analyses of cell-surface proteins identified GLAST, a glutamate-aspartate transporter that is marked reduced in Neo1 KO astrocytes and the hippocampus. NEO1 interacts with GLAST and promotes GLAST surface distribution in astrocytes. Expressing NEO1 or GLAST in Neo1 KO astrocytes in the hippocampus abolishes the epileptic phenotype. Taken together, these results uncover an unrecognized pathway of NEO1-GLAST in hippocampal GFAP+ astrocytes, which is critical for GLAST surface distribution and function, and GABAergic transmission, unveiling NEO1 as a valuable therapeutic target to protect the brain from epilepsy. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Astrocyte; Epilepsy; GLAST; Glutamate uptake; Neogenin
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179846
作者单位	Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States; Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, United States
推荐引用方式 GB/T 7714	Sun D.,Tan Z.-B.,Sun X.-D.,et al. Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response[J],2021,118(16).
APA	Sun D..,Tan Z.-B..,Sun X.-D..,Liu Z.-P..,Chen W.-B..,...&Xiong W.-C..(2021).Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Sun D.,et al."Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).