EPAC Null Mutation Impairs Learning and Social Interactions via Aberrant Regulation of miR-124 and Zif268 Translation

EPAC proteins are the guanine nucleotide exchange factors that act as the intracellular receptors for cyclic AMP. Two variants of EPAC genes including EPAC1 and EPAC2 are cloned and are widely expressed throughout the brain. But, their functions in the brain remain unknown. Here, we genetically delete EPAC1 (EPAC1−/−), EPAC2 (EPAC2−/−), or both EPAC1 and EPAC2 genes (EPAC−/−) in the forebrain of mice. We show that EPAC null mutation impairs long-term potentiation (LTP) and that this impairment is paralleled with the severe deficits in spatial learning and social interactions and is mediated in a direct manner by miR-124 transcription and Zif268 translation. Knockdown of miR-124 restores Zif268 and hence reverses all aspects of the EPAC−/− phenotypes, whereas expression of miR-124 or knockdown of Zif268 reproduces the effects of EPAC null mutation. Thus, EPAC proteins control miR-124 transcription in the brain for processing spatial learning and social interactions. ► EPAC proteins have functional redundancy in the brain ► EPAC proteins interact with miR-124 via activation of Rap1 ► miR-124 directly binds to, and inhibits, Zif268 translation ► Loss of EPAC proteins causes cognitive and social dysfunctions EPAC proteins are guanine nucleotide exchange factors that act as receptors of cyclic AMP. Yang et al. find that EPAC1 and EPAC2 proteins synergistically regulate miR-124 transcription, controlling Zif268 translation, and affect spatial learning and social interaction.