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.

Functional dissection of NEAT1 using genome editing reveals substantial localization of the NEAT1_1 isoform outside paraspeckles

“…Unsurprisingly, there is also a strong link between high NEAT1 expression and more aggressive forms of cancer (Chakravarty et al 2014;Chai et al 2016;Chen et al 2016;Fu et al 2016;Ma et al 2016;Sun et al 2016;Wang et al 2016). In neurological systems, up-regulated expression of NEAT1 has also been observed in the early phase of amyotrophic lateral sclerosis and Huntington's disease, and more interestingly, its expression could also be acutely down-regulated in response to neuronal activity (Nishimoto et al 2013;Sunwoo et al 2016;Barry et al 2017). At the molecular level, NEAT1 is important for the formation of paraspeckles, a type of mammalian nuclear RNA-protein body found in close proximity to nuclear speckles (Fox et al 2002;Hutchinson et al 2007).…”

Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol‐Response Behaviors in Model Organisms

“…Expression of the estimated 25–50K lncRNA genes in the human genome (Hangauer et al, 2013) is widespread in the brain and highly regulated (Mercer et al, 2008; Guttman et al, 2011). lncRNA are implicated in multiple neurodevelopmental, neurodegenerative and neuropsychiatric diseases, including schizophrenia (Barry et al, 2014), Alzheimer’s (Faghihi et al, 2008), autism (Kerin et al, 2012) and neuronal excitability and epilepsy (Barry et al, 2017). A recent GWAS of AD detected GWS association in the lncRNA LOC100507053 (Gelernter et al., 2014).…”

Cognitive deficits in a rat model of temporal lobe epilepsy using touchscreen‐based translational tools

“…Rats were gently handled for 2 days prior to induction of status epilepticus (SE), which was achieved via systemic administration of kainic acid (KA) using the Hellier protocol 28 (Tocris Biosciences), as described previously. 29,30 We chose to use this reliable protocol of repeated lowdoses of KA to systematically monitor the development of epilepsy (diagnosed by recurrent spontaneous seizures) and limit overdose of KA, which is a concern when large single doses are delivered. In addition, we preferred to use this model over amygdala kindling, since even after many stimulations and seizures, animals rarely develop spontaneous seizures, and true epilepsy.…”