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.

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