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Hippocampal MicroRNA-124 Enhances Chronic Stress Resilience in Mice

Higuchi, Fumihiro ; Uchida, Shusaku ; Yamagata, Hirotaka ; Abe-Higuchi, Naoko ; Hobara, Teruyuki ; Hara, Kumiko ; Kobayashi, Ayumi ; Shintaku, Tatsushi ; Itoh, Yukihiro ; Suzuki, Takayoshi ; Watanabe, Yoshifumi

The Journal of neuroscience, 2016-07, Vol.36 (27), p.7253-7267 [Periódico revisado por pares]

United States: Society for Neuroscience

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Título:
Hippocampal MicroRNA-124 Enhances Chronic Stress Resilience in Mice
Autor: Higuchi, Fumihiro ; Uchida, Shusaku ; Yamagata, Hirotaka ; Abe-Higuchi, Naoko ; Hobara, Teruyuki ; Hara, Kumiko ; Kobayashi, Ayumi ; Shintaku, Tatsushi ; Itoh, Yukihiro ; Suzuki, Takayoshi ; Watanabe, Yoshifumi
Assuntos: Animals ; Antidepressive Agents - pharmacology ; Antidepressive Agents - therapeutic use ; Depression - drug therapy ; Depression - etiology ; Disease Models, Animal ; Fluoroquinolones - pharmacology ; Food Preferences - drug effects ; Gene Expression Regulation - drug effects ; Glycogen Synthase Kinase 3 beta - metabolism ; Hippocampus - cytology ; Hippocampus - drug effects ; Hippocampus - metabolism ; Histone Deacetylases - metabolism ; Imipramine - therapeutic use ; Male ; Mice ; Mice, Inbred BALB C ; MicroRNAs - genetics ; MicroRNAs - metabolism ; Neurons - drug effects ; Neurons - pathology ; Neurons - ultrastructure ; Oligodeoxyribonucleotides, Antisense - pharmacology ; Stress, Psychological - physiopathology ; Topoisomerase II Inhibitors - pharmacology
É parte de: The Journal of neuroscience, 2016-07, Vol.36 (27), p.7253-7267
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Author contributions: F.H. and S.U. designed research; F.H., S.U., H.Y., N.A.-H., T.H., K.H., A.K., and T. Shintaku performed research; Y.I. and T. Suzuki contributed unpublished reagents/analytic tools; F.H., S.U., N.A.-H., T.H., and K.H. analyzed data; F.H., S.U., and Y.W. wrote the paper.
Descrição: Chronic stress-induced aberrant gene expression in the brain and subsequent dysfunctional neuronal plasticity have been implicated in the etiology and pathophysiology of mood disorders. In this study, we examined whether altered expression of small, regulatory, noncoding microRNAs (miRNAs) contributes to the depression-like behaviors and aberrant neuronal plasticity associated with chronic stress. Mice exposed to chronic ultra-mild stress (CUMS) exhibited increased depression-like behaviors and reduced hippocampal expression of the brain-enriched miRNA-124 (miR-124). Aberrant behaviors and dysregulated miR-124 expression were blocked by chronic treatment with an antidepressant drug. The depression-like behaviors are likely not conferred directly by miR-124 downregulation because neither viral-mediated hippocampal overexpression nor intrahippocampal infusion of an miR-124 inhibitor affected depression-like behaviors in nonstressed mice. However, viral-mediated miR-124 overexpression in hippocampal neurons conferred behavioral resilience to CUMS, whereas inhibition of miR-124 led to greater behavioral susceptibility to a milder stress paradigm. Moreover, we identified histone deacetylase 4 (HDAC4), HDAC5, and glycogen synthase kinase 3β (GSK3β) as targets for miR-124 and found that intrahippocampal infusion of a selective HDAC4/5 inhibitor or GSK3 inhibitor had antidepressant-like actions on behavior. We propose that miR-124-mediated posttranscriptional controls of HDAC4/5 and GSK3β expressions in the hippocampus have pivotal roles in susceptibility/resilience to chronic stress. Depressive disorders are a major public health concern worldwide. Although a clear understanding of the etiology of depression is still lacking, chronic stress-elicited aberrant neuronal plasticity has been implicated in the pathophysiology of depression. We show that the hippocampal expression of microRNA-124 (miR-124), an endogenous small, noncoding RNA that represses gene expression posttranscriptionally, controls resilience/susceptibility to chronic stress-induced depression-like behaviors. These effects on depression-like behaviors may be mediated through regulation of the mRNA or protein expression levels of histone deacetylases HDAC4/5 and glycogen synthase kinase 3β, all highly conserved miR-124 targets. Moreover, miR-124 contributes to stress-induced dendritic hypotrophy and reduced spine density of dentate gyrus granule neurons. Modulation of hippocampal miR-124 pathways may have potential antidepressant effects.
Editor: United States: Society for Neuroscience
Idioma: Inglês

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Hippocampal MicroRNA-124 Enhances Chronic Stress Resilience in Mice

Higuchi, Fumihiro ; Uchida, Shusaku ; Yamagata, Hirotaka ; Abe-Higuchi, Naoko ; Hobara, Teruyuki ; Hara, Kumiko ; Kobayashi, Ayumi ; Shintaku, Tatsushi ; Itoh, Yukihiro ; Suzuki, Takayoshi ; Watanabe, Yoshifumi

United States: Society for Neuroscience

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