title: Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy.
abstract: Dysfunction of fast-spiking, parvalbumin-positive (FS-PV) interneurons is implicated in the pathogenesis of epilepsy. ErbB4, a key Neuregulin 1 (NRG1) receptor, is mainly expressed in this type of interneurons, and recent studies suggest that parvalbumin interneurons are a major target of NRG1-ErbB4 signaling in adult brain. Thus, we hypothesized that downregulation of NRG1-ErbB4 signaling in FS-PV interneurons is involved in epilepsy. We found that NRG1, through its receptor ErbB4, increased the intrinsic excitability of FS-PV interneurons. This effect was mediated by increasing the near-threshold responsiveness and decreasing the voltage threshold for action potentials through Kv1.1, a voltage-gated potassium channel. Furthermore, mice with specific deletion of ErbB4 in parvalbumin interneurons were more susceptible to pentylenetetrazole- and pilocarpine-induced models of epilepsy. Exogenous NRG1 delayed the onset of seizures and decreased their incidence and stage. Moreover, expression of ErbB4, but not ErbB2, was downregulated in human epileptogenic tissue. Together, our findings suggest that NRG1-ErbB4 signaling contributes to human epilepsy through regulating the excitability of FS-PV interneurons. ErbB4 may be a new target for anticonvulsant drugs in epilepsy.
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Ke-Xin
authors.initials: KX
authors.lastname: Li
authors.forename: Ying-Mei
authors.initials: YM
authors.lastname: Lu
authors.forename: Zheng-Hao
authors.initials: ZH
authors.lastname: Xu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Jun-Ming
authors.initials: JM
authors.lastname: Zhu
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Zhang
authors.forename: Shu-Xia
authors.initials: SX
authors.lastname: Cao
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Chen
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Luo
authors.forename: Shumin
authors.initials: S
authors.lastname: Duan
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Li
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001703:Biophysics; D051242:Caveolin 1 / Q000378:metabolism; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004558:Electric Stimulation; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D051662:Kv1.1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010433:Pentylenetetrazole / Q000633:toxicity; D010455:Peptides / Q000494:pharmacology; D010862:Pilocarpine / Q000633:toxicity; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D051242:Caveolin 1; D066246:ErbB Receptors; D051662:Kv1.1 Potassium Channel; D020890:Neuregulin-1; D010320:Parvalbumins; D010433:Pentylenetetrazole; D010455:Peptides; D010862:Pilocarpine; D026902:Potassium Channel Blockers; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D020032:Tyrphostins; C495540:CAV1 protein, human; C490581:Nrg1 protein, mouse; C081506:dendrotoxin K; C101044:RTKI cpd; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse