The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states

Guy Barry, James A. Briggs, Do Won Hwang, Sam P. Nayler, Patrick R J Fortuna, Nicky Jonkhout, Fabien Dachet, Jesper L V Maag, Pieter Mestdagh, Erin M. Singh, Lotta Avesson, Dominik C. Kaczorowski, Ezgi Ozturk, Nigel C. Jones, Irina Vetter, Luis Arriola-Martinez, Jianfei Hu, Gloria R. Franco, Victoria M. Warn, Andrew Gong & 10 others Marcel E. Dinger, Frank Rigo, Leonard Lipovich, Margaret J. Morris, Terence J. O'Brien, Dong Soo Lee, Jeffrey A. Loeb, Seth Blackshaw, John S. Mattick, Ernst J. Wolvetang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number40127
JournalScientific Reports
Volume7
DOIs
StatePublished - Jan 5 2017

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Long Noncoding RNA
Kv Channel-Interacting Proteins
Epilepsy
Seizures
Neurons
Temporal Lobe Epilepsy
Antisense Oligonucleotides
Ion Channels
Human Activities
Nervous System
Phenotype
Gene Expression

ASJC Scopus subject areas

  • General

Cite this

Barry, G., Briggs, J. A., Hwang, D. W., Nayler, S. P., Fortuna, P. R. J., Jonkhout, N., ... Wolvetang, E. J. (2017). The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states. Scientific Reports, 7, [40127]. https://doi.org/10.1038/srep40127

The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states. / Barry, Guy; Briggs, James A.; Hwang, Do Won; Nayler, Sam P.; Fortuna, Patrick R J; Jonkhout, Nicky; Dachet, Fabien; Maag, Jesper L V; Mestdagh, Pieter; Singh, Erin M.; Avesson, Lotta; Kaczorowski, Dominik C.; Ozturk, Ezgi; Jones, Nigel C.; Vetter, Irina; Arriola-Martinez, Luis; Hu, Jianfei; Franco, Gloria R.; Warn, Victoria M.; Gong, Andrew; Dinger, Marcel E.; Rigo, Frank; Lipovich, Leonard; Morris, Margaret J.; O'Brien, Terence J.; Lee, Dong Soo; Loeb, Jeffrey A.; Blackshaw, Seth; Mattick, John S.; Wolvetang, Ernst J.

In: Scientific Reports, Vol. 7, 40127, 05.01.2017.

Research output: Contribution to journalArticle

Barry, G, Briggs, JA, Hwang, DW, Nayler, SP, Fortuna, PRJ, Jonkhout, N, Dachet, F, Maag, JLV, Mestdagh, P, Singh, EM, Avesson, L, Kaczorowski, DC, Ozturk, E, Jones, NC, Vetter, I, Arriola-Martinez, L, Hu, J, Franco, GR, Warn, VM, Gong, A, Dinger, ME, Rigo, F, Lipovich, L, Morris, MJ, O'Brien, TJ, Lee, DS, Loeb, JA, Blackshaw, S, Mattick, JS & Wolvetang, EJ 2017, 'The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states', Scientific Reports, vol. 7, 40127. https://doi.org/10.1038/srep40127
Barry, Guy ; Briggs, James A. ; Hwang, Do Won ; Nayler, Sam P. ; Fortuna, Patrick R J ; Jonkhout, Nicky ; Dachet, Fabien ; Maag, Jesper L V ; Mestdagh, Pieter ; Singh, Erin M. ; Avesson, Lotta ; Kaczorowski, Dominik C. ; Ozturk, Ezgi ; Jones, Nigel C. ; Vetter, Irina ; Arriola-Martinez, Luis ; Hu, Jianfei ; Franco, Gloria R. ; Warn, Victoria M. ; Gong, Andrew ; Dinger, Marcel E. ; Rigo, Frank ; Lipovich, Leonard ; Morris, Margaret J. ; O'Brien, Terence J. ; Lee, Dong Soo ; Loeb, Jeffrey A. ; Blackshaw, Seth ; Mattick, John S. ; Wolvetang, Ernst J. / The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states. In: Scientific Reports. 2017 ; Vol. 7.
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AU - Barry, Guy

AU - Briggs, James A.

AU - Hwang, Do Won

AU - Nayler, Sam P.

AU - Fortuna, Patrick R J

AU - Jonkhout, Nicky

AU - Dachet, Fabien

AU - Maag, Jesper L V

AU - Mestdagh, Pieter

AU - Singh, Erin M.

AU - Avesson, Lotta

AU - Kaczorowski, Dominik C.

AU - Ozturk, Ezgi

AU - Jones, Nigel C.

AU - Vetter, Irina

AU - Arriola-Martinez, Luis

AU - Hu, Jianfei

AU - Franco, Gloria R.

AU - Warn, Victoria M.

AU - Gong, Andrew

AU - Dinger, Marcel E.

AU - Rigo, Frank

AU - Lipovich, Leonard

AU - Morris, Margaret J.

AU - O'Brien, Terence J.

AU - Lee, Dong Soo

AU - Loeb, Jeffrey A.

AU - Blackshaw, Seth

AU - Mattick, John S.

AU - Wolvetang, Ernst J.

PY - 2017/1/5

Y1 - 2017/1/5

N2 - 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.

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