Bidirectional Impact of miR-29a modulation on Memory Stability in the Adult Brain
MicroRNAs are key regulators of brain gene expression, with miR-29a 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-29a levels in the dorsal hippocampus of adult mice to reveal miR-29 role in memory. Inhibiting miR-29a enhanced trace fear memory stability, increased Dnmt3a levels, and affected CpG methylation in gene regulation regions. In contrast, increasing miR-29a impaired memory performances and decreased Dnmt3a levels, suggesting a destabilization of memory processes. Proteomic and transcriptomic analysis demonstrated that miR-29a antagonism upregulated RNA-binding and synaptic proteins and downregulated inflammation and myelin associated proteins. These results underscore miR-29a pivotal role in memory persistence, plasticity, and cognitive aging, suggesting that miR-29a modulation could offer potential strategies for cognitive enhancement and age-related memory decline.