title: The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states.
abstract: Despite their abundance, the molecular functions of long non-coding RNAs in mammalian nervous systems remain poorly understood. Here we show that the long non-coding RNA, NEAT1, directly modulates neuronal excitability and is associated with pathological seizure states. Specifically, NEAT1 is dynamically regulated by neuronal activity in vitro and in vivo, binds epilepsy-associated potassium channel-interacting proteins including KCNAB2 and KCNIP1, and induces a neuronal hyper-potentiation phenotype in iPSC-derived human cortical neurons following antisense oligonucleotide knockdown. Next generation sequencing reveals a strong association of NEAT1 with increased ion channel gene expression upon activation of iPSC-derived neurons following NEAT1 knockdown. Furthermore, we show that while NEAT1 is acutely down-regulated in response to neuronal activity, repeated stimulation results in NEAT1 becoming chronically unresponsive in independent in vivo rat model systems relevant to temporal lobe epilepsy. We extended previous studies showing increased NEAT1 expression in resected cortical tissue from high spiking regions of patients suffering from intractable seizures. Our results indicate a role for NEAT1 in modulating human neuronal activity and suggest a novel mechanistic link between an activity-dependent long non-coding RNA and epilepsy.
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.|Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Guy
authors.initials: G
authors.lastname: Barry
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: Briggs
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Do Won
authors.initials: DW
authors.lastname: Hwang
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Sam P
authors.initials: SP
authors.lastname: Nayler
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Patrick R J
authors.initials: PR
authors.lastname: Fortuna
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Nicky
authors.initials: N
authors.lastname: Jonkhout
authors.affiliation: Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Dachet
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St Vincent's Clinical School, UNSW Australia, Kensington NSW 2052, Australia.
authors.forename: Jesper L V
authors.initials: JL
authors.lastname: Maag
authors.affiliation: Center for Medical Genetics, Ghent University 9000, Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Mestdagh
authors.affiliation: Department of Neuroscience, Neurology and Ophthalmology, Center for High-Throughput Biology and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Singh
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Lotta
authors.initials: L
authors.lastname: Avesson
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Dominik C
authors.initials: DC
authors.lastname: Kaczorowski
authors.affiliation: Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Parkville 3050, Victoria, Australia.
authors.forename: Ezgi
authors.initials: E
authors.lastname: Ozturk
authors.affiliation: Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Parkville 3050, Victoria, Australia.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Jones
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia 4072, Queensland, Australia.
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Luis
authors.initials: L
authors.lastname: Arriola-Martinez
authors.affiliation: Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Hu
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais Belo Horizonte, Brazil.
authors.forename: Gloria R
authors.initials: GR
authors.lastname: Franco
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Warn
authors.affiliation: School of Medical Sciences, University of New South Wales, New South Wales 2052, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gong
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|St Vincent's Clinical School, UNSW Australia, Kensington NSW 2052, Australia.|Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors.forename: Marcel E
authors.initials: ME
authors.lastname: Dinger
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA 92010, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.|Department of Neurology, Wayne State University School of Medicine, Detroit, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Lipovich
authors.affiliation: Department of Pharmacology, University of New South Wales, New South Wales 2052, Australia.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Morris
authors.affiliation: Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Parkville 3050, Victoria, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Loeb
authors.affiliation: Department of Neuroscience, Neurology and Ophthalmology, Center for High-Throughput Biology and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.|St Vincent's Clinical School, UNSW Australia, Kensington NSW 2052, Australia.
authors.forename: John S
authors.initials: JS
authors.lastname: Mattick
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Wolvetang
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology*; D002478:Cells, Cultured; D000071080:Cortical Excitability; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000378:metabolism*; D051381:Rats; D012640:Seizures / Q000473:pathology*; D051637:Shaker Superfamily of Potassium Channels
chemical_list: C498948:KCNAB2 protein, human; C496750:KCNIP1 protein, human; D051605:Kv Channel-Interacting Proteins; C577276:NEAT1 long non-coding RNA, human; D024642:Potassium Channels, Voltage-Gated; D062085:RNA, Long Noncoding; D051637:Shaker Superfamily of Potassium Channels