Abstract
De novo protein synthesis supports long-lasting functional and structural plasticity and is a molecular requirement for new memory formation. Recent evidence has suggested that microRNAs may be involved in regulating the molecular mechanisms underlying neural plasticity. MicroRNAs are endogenous, noncoding RNAs capable of post-transcriptional repression of their mRNA targets. To explore the potential for microRNA-mediated regulation of amygdala-dependent memory formation, we performed expression profiling of microRNAs in the lateral amygdala of rats 1 h after auditory fear conditioning. Microarray analysis revealed that over half of all known microRNAs are endogenously expressed in the lateral amygdala, with 7 microRNAs upregulated and 32 downregulated by auditory fear training. Bioinformatic analysis identified several of the downregulated microRNAs as potential repressors of actin-regulating proteins known to be involved in plasticity and memory. Downregulation of one of these microRNAs by auditory fear conditioning, miR-182, was confirmed by quantitative real-time PCR. Overexpression of miR-182 within the lateral amygdala resulted in decreased expression of the protein but not mRNA of two synapse-enriched regulators of actin known to modulate structural plasticity, cortactin and Rac1. The overexpression of miR-182 also disrupted long-term but not short-term auditory fear memory. These data indicate that learning-induced suppression of miR-182, a microRNA previously uncharacterized in the brain, supports long-term memory formation in the amygdala and suggests it does so, at least in part, through the derepression of key actin-regulating proteins. These findings further indicate that microRNAs may represent a previously underappreciated mechanism for regulating protein synthesis during memory consolidation.