The DNA repair associated protein Gadd45γ regulates the temporal coding of immediate early gene expression and is required for the consolidation of associative fear memory

Visual abstract We have identified a member of the Growth arrest and DNA damage (Gadd45) family, Gadd45 γ , which is known to be involved in the regulation of DNA repair, as a key player in the formation of associative fear memory. Gadd45 γ regulates the temporal dynamics of learning-induced immediate early gene (IEG) expression in the prelimbic prefrontal cortex 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 followed by an increase in DNA methylation, and 2) a second wave of IEG expression associated with Gadd45 γ 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 GADD45γ, 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 γ 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.