MicroRNA-mediated rescue of fear extinction memory by miR-144-3p in extinction-impaired mice

Murphy, Conor P., Li, Xiang, Maurer, Verena, Oberhauser, Michael, Gstir, Ronald, Wearick-Silva, Luis Eduardo, Viola, Thiago Wendt, Schafferer, Simon, Grassi-Oliverira, Rodrigo, Whittle, Nigel, Huttenhofer, Alexander, Bredy, Timothy W. and Singewald, Nicolas (2016) MicroRNA-mediated rescue of fear extinction memory by miR-144-3p in extinction-impaired mice. Biological Psychiatry, . doi:10.1016/j.biopsych.2016.12.021

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Author Murphy, Conor P.
Li, Xiang
Maurer, Verena
Oberhauser, Michael
Gstir, Ronald
Wearick-Silva, Luis Eduardo
Viola, Thiago Wendt
Schafferer, Simon
Grassi-Oliverira, Rodrigo
Whittle, Nigel
Huttenhofer, Alexander
Bredy, Timothy W.
Singewald, Nicolas
Title MicroRNA-mediated rescue of fear extinction memory by miR-144-3p in extinction-impaired mice
Journal name Biological Psychiatry   Check publisher's open access policy
ISSN 1873-2402
0006-3223
1086-7694
Publication date 2016-12-26
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.biopsych.2016.12.021
Open Access Status File (Author Post-print)
Total pages 11
Place of publication Philadelphia, PA United States
Publisher Elsevier
Collection year 2017
Language eng
Formatted 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.
Keyword Anxiety- and trauma-related disorders
Basolateral amygdala, Fear
MicroRNAs
PI3K/AKT
Signaling cascade modulation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
 
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