Abstract
Activity-dependent alteration of the transcriptional program is central for shaping neuronal connectivity. Constitutively expressed transcription factors orchestrate the initial response to neuronal stimulation and serve as substrates for second messenger-regulated kinase signalling cascades. The mitogen-activated protein kinase ERK conveys signalling from the synapse to the nucleus but its genetic signature following neuronal activity has not been revealed. The goal of the present study was to identify ERK dependent and independent activity regulated transcriptional programs in the murine hippocampus. We used generalized seizures combined with the pharmacological intervention of MEK activation as an in vivo model to determine the complete transcriptional program initiated by ERK after neuronal activity. Our survey demonstrates that the induction of a large number of activity-regulated genes, including Arc/Arg3.1, Arl5b, Gadd45b, Homer1, Inhba and Zwint, is indeed dependent on ERK phosphorylation. In contrast, expression of a small group of genes, including Npas4, Arl4d, Errfi1, and Rgs2, is only partially dependent or completely independent (Ppp1r15a) of this signalling pathway. Among the identified transcripts are long non-coding (lnc) RNAs and induction of LincPint and splice variants of NEAT1 are ERK dependent. Our survey provides a comprehensive analysis of the transcriptomic response conveyed by ERK signalling in the hippocampus.
Highlights
That ERK activation is important for LTD and plays a critical role in mammalian learning and memory[15,16,17,18,19,20,21,22]
The distinct pattern of ERK phosphorylation in the hippocampus in response to increased global neuronal activity provoked by seizures is in agreement with previous studies employing kainic acid or electroconvulsive seizures or long term potentiation (LTP)[24,27,35]
We used seizures combined with the pharmacological intervention of MEK activation as an in vivo model to determine genome wide the transcriptional program initiated by the MAPK/ERK signalling pathway after neuronal activity in the murine hippocampus
Summary
That ERK activation is important for LTD and plays a critical role in mammalian learning and memory[15,16,17,18,19,20,21,22]. Additional studies suggest that ERK phosphorylation is required for proper development of neuronal functions and its inhibition leads to the development of autistic phenotypes in mice[23]. The transcriptional program in neurons initiated by ERK has only been partially elucidated. Most studies used a candidate gene approach rather than performing a genome wide analysis. Our objective was to determine the transcriptional program initiated by ERK after neuronal activity in the murine hippocampus. To this end, we used chemically provoked seizures to induce strong, synchronized neuronal activity in combination with the MEK inhibitor SL327 and performed a genome wide analysis of the initiated transcriptional program
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