Mathew, Rebecca STatarakis, AntonisRudenko, AndriiJohnson-Venkatesh, Erin MYang, Yawei JMurphy, Elisabeth ATodd, Travis PSchepers, Scott TSiuti, NertilaMartorell, Anthony JFalls, William AHammack, Sayamwong EWalsh, ChristopherTsai, Li-HueiUmemori, HisashiBouton, Mark EMoazed, Danesh2017-03-282016Mathew, R. S., A. Tatarakis, A. Rudenko, E. M. Johnson-Venkatesh, Y. J. Yang, E. A. Murphy, T. P. Todd, et al. 2016. “A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory.” eLife 5 (1): e22467. doi:10.7554/eLife.22467. http://dx.doi.org/10.7554/eLife.22467.http://nrs.harvard.edu/urn-3:HUL.InstRepos:31731816The SNARE-mediated vesicular transport pathway plays major roles in synaptic remodeling associated with formation of long-term memories, but the mechanisms that regulate this pathway during memory acquisition are not fully understood. Here we identify miRNAs that are up-regulated in the rodent hippocampus upon contextual fear-conditioning and identify the vesicular transport and synaptogenesis pathways as the major targets of the fear-induced miRNAs. We demonstrate that miR-153, a member of this group, inhibits the expression of key components of the vesicular transport machinery, and down-regulates Glutamate receptor A1 trafficking and neurotransmitter release. MiR-153 expression is specifically induced during LTP induction in hippocampal slices and its knockdown in the hippocampus of adult mice results in enhanced fear memory. Our results suggest that miR-153, and possibly other fear-induced miRNAs, act as components of a negative feedback loop that blocks neuronal hyperactivity at least partly through the inhibition of the vesicular transport pathway. DOI: http://dx.doi.org/10.7554/eLife.22467.001en-USlearningmemorysynaptic plasticitymiRNAhippocampusnegative feed back loopRatMouseJournal Article2017-03-2810.7554/eLife.22467