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Biol Psychiatry. 2017 Jun 15;81(12):979-989. doi: 10.1016/j.biopsych.2016.12.021. Epub 2016 Dec 26.

MicroRNA-Mediated Rescue of Fear Extinction Memory by miR-144-3p in Extinction-Impaired Mice.

Author information

1
Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck.
2
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California.
3
Division of Genomics and RNomics, Biocenter Innsbruck, Innsbruck Medical University, Innsbruck, Austria.
4
Developmental Cognitive Neuroscience Research Group (GNCD), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
5
Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
6
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California; Queensland Brain Institute, University of Queensland, Brisbane, Australia.
7
Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck. Electronic address: nicolas.singewald@uibk.ac.at.

Abstract

BACKGROUND:

MicroRNA (miRNA)-mediated control of gene expression suggests that miRNAs are interesting targets and/or biomarkers in the treatment of anxiety- and trauma-related disorders, where often memory-associated gene expression is adversely affected.

METHODS:

The role of miRNAs in the rescue of impaired fear extinction was assessed using the 129S1/SvlmJ (S1) mouse model of impaired fear extinction. miRNA microarray analysis, reverse transcription polymerase chain reaction, fluorescent in situ hybridization, lentiviral overexpression, and Luciferase reporter assays were used to gain insight into the mechanisms underlying miRNA-mediated normalization of deficient fear extinction.

RESULTS:

Rescuing impaired fear extinction via dietary zinc restriction was associated with differential expression of miRNAs in the amygdala. One candidate, miR-144-3p, robustly expressed in the basolateral amygdala, showed specific extinction-induced, but not fear-induced, increased expression in both extinction-rescued S1 mice and extinction-intact C57BL/6 (BL6) mice. miR-144-3p upregulation and effects on subsequent behavioral adaption was assessed in S1 and BL6 mice. miR-144-3p overexpression in the basolateral amygdala rescued impaired fear extinction in S1 mice, led to enhanced fear extinction acquisition in BL6 mice, and furthermore protected against fear renewal in BL6 mice. miR-144-3p targets a number of genes implicated in the control of plasticity-associated signaling cascades, including Pten, Spred1, and Notch1. In functional interaction studies, we revealed that the miR-144-3p target, PTEN, colocalized with miR-144-3p in the basolateral amygdala and showed functional downregulation following successful fear extinction in S1 mice.

CONCLUSIONS:

These findings identify a fundamental role of miR-144-3p in the rescue of impaired fear extinction and suggest this miRNA as a viable target in developing novel treatments for posttraumatic stress disorder and related disorders.

KEYWORDS:

Anxiety- and trauma-related disorders; Basolateral amygdala, Fear; MicroRNAs; PI3K/AKT; Signaling cascade modulation

PMID:
28104225
DOI:
10.1016/j.biopsych.2016.12.021
[Indexed for MEDLINE]
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