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

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 dynami...

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Published in:	Scientific reports Vol. 7; no. 1; p. 40127
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 05-01-2017 Nature Publishing Group
Subjects:	13/106 45/100 631/378/340 631/532/2064 82/51 82/79 Antisense oligonucleotides Epilepsy Excitability Firing pattern Gene expression Humanities and Social Sciences multidisciplinary Non-coding RNA Potentiation Rodents Science Science (multidisciplinary) Seizures Temporal lobe
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/srep40127