A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory
Rebecca S Mathew,
Antonis Tatarakis,
Andrii Rudenko,
Erin M Johnson-Venkatesh,
Yawei J Yang,
Elisabeth A Murphy,
Travis P Todd,
Scott T Schepers,
Nertila Siuti,
Anthony J Martorell,
William A Falls,
Sayamwong E Hammack,
Christopher A Walsh,
Li-Huei Tsai,
Hisashi Umemori,
Mark E Bouton,
Danesh Moazed
Affiliations
Rebecca S Mathew
Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
Antonis Tatarakis
Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
Andrii Rudenko
Department of Brain and Cognitive Sciences Massachusetts Institute of Technology, The Picower Institute for Learning and Memory, Cambridge, United States
Erin M Johnson-Venkatesh
Department of Neurology, FM Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, United States
Yawei J Yang
Division of Genetics, Howard Hughes Medical Institute, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, United States; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, United States; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, United States
Elisabeth A Murphy
Division of Genetics, Howard Hughes Medical Institute, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, United States
Travis P Todd
Department of Psychology, University of Vermont, Burlington, United States
Department of Psychology, University of Vermont, Burlington, United States
Nertila Siuti
Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
Anthony J Martorell
Department of Brain and Cognitive Sciences Massachusetts Institute of Technology, The Picower Institute for Learning and Memory, Cambridge, United States
William A Falls
Department of Psychology, University of Vermont, Burlington, United States
Sayamwong E Hammack
Department of Psychology, University of Vermont, Burlington, United States
Christopher A Walsh
Division of Genetics, Howard Hughes Medical Institute, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, United States; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
Li-Huei Tsai
Department of Brain and Cognitive Sciences Massachusetts Institute of Technology, The Picower Institute for Learning and Memory, Cambridge, United States; Broad Institute of MIT and Harvard, Cambridge, United States
The 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.
