The DNA Repair-Associated Protein Gadd45 gamma Regulates the Temporal Coding of Immediate Early Gene Expression within the Prelimbic Prefrontal Cortex and Is Required for the Consolidation of Associative Fear Memory

Li, X; Marshall, PR; Leighton, LJ; Zajaczkowski, EL; Wang, ZQ; Madugalle, SU; Yin, JY; Bredy, TW; Wei, W

Bredy, TW; Wei, W (reprint author), Univ Queensland, Queensland Brain Inst, Cognit Neuroepigenet Lab, St Lucia, Qld 4072, Australia.

JOURNAL OF NEUROSCIENCE, 2019; 39 (6): 970

Abstract

We have identified a member of the growth arrest and DNA damage (Gadd45) protein family, Gadd45 gamma, 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 C57BL/6 mice. Gadd45 gamma 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 gamma and active DNA demethylation at the same site, which is necessary for memory consolidation.

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