MicroRNA-29 acutely regulates memory stability, expression of synaptic genes, and DNA methylation in the mouse adult hippocampus

: MicroRNAs are key regulators of brain gene expression, with miR-29 family notably upregulated from development to adulthood and in aging, and showing links to cognitive decline. However, the extent to which miR-29 levels influence learning and memory processes, and its molecular mediators, remains to be determined. Here, we down- and up-regulated miR-29 levels in the dorsal hippocampus of adult mice to reveal miR-29 role in memory. Inhibition of miR-29 enhanced trace fear memory stability, increased Dnmt3a levels, and promoted DNA methylation in a DNMT3a-dependent manner. In contrast, increasing miR-29 impaired memory performances and decreased Dnmt3a levels, suggesting a destabilization of memory processes. Proteomic and transcriptomic analysis demonstrated that miR-29 antagonism upregulated RNA-binding and synaptic proteins and downregulated inflammation and myelin associated proteins. These results underscore miR-29's pivotal role in memory persistence, plasticity, and cognitive aging, suggesting that miR-29 modulation could offer potential strategies for cognitive enhancement and age-related memory decline.