The DNA repair associated protein Gadd45 ׆ regulates the temporal coding of immediate early gene expression within the prelimbic prefrontal cortex and is required for the consolidation of associative fear memory.

We have identified a member of the growth arrest and DNA damage (Gadd45) protein family, Gadd45 ׆ , which is known to be critically involved in DNA repair, as a key player in the regulation of immediate early gene (IEG) expression underlying the consolidation of associative fear memory in adult male C57/Bl6 mice. Gadd45 ׆ temporally influences learning-induced IEG expression in the prelimbic prefrontal cortex (PLPFC) through its interaction with DNA double-strand break (DSB)-mediated changes in DNA methylation. Our findings suggest a two-hit model of experience-dependent IEG activity and learning that comprises 1) a first wave of IEG expression governed by DSBs and followed by a rapid increase in DNA methylation, and 2) a second wave of IEG expression associated with the recruitment of Gadd45 ׆ and active DNA demethylation at the same site, which is necessary for memory consolidation. Significance statement: How does the pattern of immediate early gene (IEG) transcription in the brain relate to the storage and accession of information, and what controls these patterns? This paper explores how Gadd45 ׆ , a gene that is known to be involved with DNA modification and repair, regulates the temporal coding of IEGs underlying associative learning and memory. We reveal that, during fear learning, Gadd45 ׆ serves to act as a coordinator of IEG expression and subsequent memory consolidation by directing temporally specific changes in active DNA demethylation at the promoter of plasticity-related IEGs.