PPM1F in Dentate Gyrus Modulates Anxiety-Related Behaviors by Regulating BDNF Expression via AKT/JNK/p-H3S10 Pathway

Anxiety is a serious psychiatric disorder, with a higher incidence rate in women than in men. Protein phosphatase Mg 2+ /Mn 2+ -dependent 1F (PPM1F), a serine/threonine phosphatase, has been shown to have multiple biological and cellular functions. However, the effects of PPM1F and its neuronal subs...

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Veröffentlicht in:Molecular neurobiology 2021-07, Vol.58 (7), p.3529-3544
Hauptverfasser: Meng, Fantao, Liu, Jing, Dai, Juanjuan, Lian, Haifeng, Jiang, Shujun, Li, Qiongyu, Wu, Min, Wang, Wentao, Wang, Dan, Zhao, Di, Liu, Cuilan, Qiu, Changyun, Li, Chen
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container_end_page 3544
container_issue 7
container_start_page 3529
container_title Molecular neurobiology
container_volume 58
creator Meng, Fantao
Liu, Jing
Dai, Juanjuan
Lian, Haifeng
Jiang, Shujun
Li, Qiongyu
Wu, Min
Wang, Wentao
Wang, Dan
Zhao, Di
Liu, Cuilan
Qiu, Changyun
Li, Chen
description Anxiety is a serious psychiatric disorder, with a higher incidence rate in women than in men. Protein phosphatase Mg 2+ /Mn 2+ -dependent 1F (PPM1F), a serine/threonine phosphatase, has been shown to have multiple biological and cellular functions. However, the effects of PPM1F and its neuronal substrates on anxiety remain largely unclear. In this study, we showed that chronic restraint stress (CRS) induced anxiety-related behaviors only in female mice, while acute restraint stress (ARS) produced anxiety-related behaviors in both male and female mice in light–dark and elevated plus maze tests and induced upregulation of PPM1F and downregulation of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Adeno-associated virus–mediated overexpression of PPM1F or conditional knockout of BDNF in dentate gyrus (DG) led to a more pronounced anxiety-related behavior in female than in male mice as indicated by the behavioral evaluations. Meanwhile, overexpression of PPM1F in the DG decreased total Bdnf exon–specific messenger RNA expression in the hippocampus with the decreased binding activity of phosphorylated H3S10 to its individual promoters in female mice. Furthermore, we identified that overexpression of PPM1F decreased the phosphorylation levels of AKT and JNK in the hippocampus of female mice. These results may suggest that PPM1F regulates anxiety-related behaviors by modulating BDNF expression and H3S10 phosphorylation–mediated epigenetic modification, which may be served as potentially pathological genes associated with anxiety or other mental diseases.
doi_str_mv 10.1007/s12035-021-02340-x
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Protein phosphatase Mg 2+ /Mn 2+ -dependent 1F (PPM1F), a serine/threonine phosphatase, has been shown to have multiple biological and cellular functions. However, the effects of PPM1F and its neuronal substrates on anxiety remain largely unclear. In this study, we showed that chronic restraint stress (CRS) induced anxiety-related behaviors only in female mice, while acute restraint stress (ARS) produced anxiety-related behaviors in both male and female mice in light–dark and elevated plus maze tests and induced upregulation of PPM1F and downregulation of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Adeno-associated virus–mediated overexpression of PPM1F or conditional knockout of BDNF in dentate gyrus (DG) led to a more pronounced anxiety-related behavior in female than in male mice as indicated by the behavioral evaluations. Meanwhile, overexpression of PPM1F in the DG decreased total Bdnf exon–specific messenger RNA expression in the hippocampus with the decreased binding activity of phosphorylated H3S10 to its individual promoters in female mice. Furthermore, we identified that overexpression of PPM1F decreased the phosphorylation levels of AKT and JNK in the hippocampus of female mice. 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Liu, Jing ; Dai, Juanjuan ; Lian, Haifeng ; Jiang, Shujun ; Li, Qiongyu ; Wu, Min ; Wang, Wentao ; Wang, Dan ; Zhao, Di ; Liu, Cuilan ; Qiu, Changyun ; Li, Chen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-a88e4d82c24367d311b97556a6cb8efd7b08ac53a751de451fe61747919e754d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>AKT protein</topic><topic>Animals</topic><topic>Anxiety</topic><topic>Anxiety - metabolism</topic><topic>Anxiety - prevention &amp; control</topic><topic>Anxiety - psychology</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain-derived neurotrophic factor</topic><topic>Brain-Derived Neurotrophic Factor - biosynthesis</topic><topic>Brain-Derived Neurotrophic Factor - genetics</topic><topic>Cell Biology</topic><topic>Dentate gyrus</topic><topic>Dentate Gyrus - metabolism</topic><topic>Epigenetics</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Hippocampus</topic><topic>Histones - metabolism</topic><topic>Magnesium</topic><topic>Male</topic><topic>MAP Kinase Signaling System - physiology</topic><topic>Mental disorders</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Neurobiology</topic><topic>Neurology</topic><topic>Neurosciences</topic><topic>Phosphatase</topic><topic>Phosphoprotein Phosphatases - biosynthesis</topic><topic>Phosphoprotein Phosphatases - genetics</topic><topic>Phosphorylation</topic><topic>Protein phosphatase</topic><topic>Protein-serine/threonine phosphatase</topic><topic>Proto-Oncogene Proteins c-akt - antagonists &amp; 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subjects AKT protein
Animals
Anxiety
Anxiety - metabolism
Anxiety - prevention & control
Anxiety - psychology
Biomedical and Life Sciences
Biomedicine
Brain-derived neurotrophic factor
Brain-Derived Neurotrophic Factor - biosynthesis
Brain-Derived Neurotrophic Factor - genetics
Cell Biology
Dentate gyrus
Dentate Gyrus - metabolism
Epigenetics
Female
Gene Expression
Hippocampus
Histones - metabolism
Magnesium
Male
MAP Kinase Signaling System - physiology
Mental disorders
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurobiology
Neurology
Neurosciences
Phosphatase
Phosphoprotein Phosphatases - biosynthesis
Phosphoprotein Phosphatases - genetics
Phosphorylation
Protein phosphatase
Protein-serine/threonine phosphatase
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - metabolism
Rodents
Serine
Threonine phosphatase
title PPM1F in Dentate Gyrus Modulates Anxiety-Related Behaviors by Regulating BDNF Expression via AKT/JNK/p-H3S10 Pathway
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