title: NR4A1 Knockdown Suppresses Seizure Activity by Regulating Surface Expression of NR2B.
abstract: Nuclear receptor subfamily 4 group A member 1 (NR4A1), a downstream target of CREB that is a key regulator of epileptogenesis, has been implicated in a variety of biological processes and was previously identified as a seizure-associated molecule. However, the relationship between NR4A1 and epileptogenesis remains unclear. Here, we showed that NR4A1 protein was predominantly expressed in neurons and up-regulated in patients with epilepsy as well as pilocarpine-induced mouse epileptic models. NR4A1 knockdown by lentivirus transfection (lenti-shNR4A1) alleviated seizure severity and prolonged onset latency in mouse models. Moreover, reciprocal coimmunoprecipitation of NR4A1 and NR2B demonstrated their interaction. Furthermore, the expression of p-NR2B (Tyr1472) in epileptic mice and the expression of NR2B in the postsynaptic density (PSD) were significantly reduced in the lenti-shNR4A1 group, indicating that NR4A1 knockdown partly decreased surface NR2B by promoting NR2B internalization. These results are the first to indicate that the expression of NR4A1 in epileptic brain tissues may provide new insights into the molecular mechanisms underlying epilepsy.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
authors.forename: Yanke
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chongqing General Hospital, 104 Pipashan Street, Chongqing 400010, China.
authors.forename: Baobing
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Neurosurgery, The Affiliated Children's Hospital of Capital Institute of Pediatrics, 2 Yabao Road, Beijing 100020, China.
authors.forename: Yunlin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of PLA General Hospital, 51 Fucheng Road, Beijing 100048, China.
authors.forename: Shuli
authors.initials: S
authors.lastname: Liang
authors.affiliation: Department of Neurology, The Affiliated Children's Hospital, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100032, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.|Center of Epilepsy, Beijing Institute for Brain Disorders, 10 Xitoutiao, Youanmen, Fengtai District, Beijing 100069, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
authors.forename: Binglin
authors.initials: B
authors.lastname: Zhu
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001522:Behavior, Animal; D016022:Case-Control Studies; D002648:Child; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D016086:Lentivirus / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D010862:Pilocarpine; D034741:RNA, Small Interfering / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012640:Seizures / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D055815:Young Adult
chemical_list: C121001:NR2B NMDA receptor; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D010862:Pilocarpine; D049452:Green Fluorescent Proteins