Gadd45a modulates aversive learning through post-transcriptional regulation of memory-related mRNAs

Learning is essential for survival, and is controlled by complex molecular mechanisms including regulation of newly synthesized mRNAs that are required to modify synaptic functions. Despite of the well-known role of RNA-binding proteins (RBPs) in mRNA functionality, their detailed regulation during memory consolidation is poorly understood. This study focuses on the brain function of the RBP Gadd45a (Growth arrest and DNA damage-inducible protein 45 alpha, encoded by the Gadd45a gene). Here, we find that hippocampal memory and long-term potentiation are strongly impaired in Gadd45a-deficient mice, a phenotype accompanied by reduced levels of memory-related mRNAs. The majority of the Gadd45a-regulated transcripts show unusually long 3´ untranslated regions (3´UTRs) that are destabilized in Gadd45a-deficient mice via a transcription-independent mechanism, leading to reduced levels of the corresponding proteins in synaptosomes. Moreover, Gadd45a can bind specifically to these memory-related mRNAs. Our study reveals a new function for extended 3´UTRs in memory consolidation and identifies Gadd45a as a novel regulator of mRNA stability. Overall design: Gene expression profiling by RNA-seq of hippocampi from wild type and Gadd45a-knockout mice subjected to the passive avoidance (PA) test