MiR-137 Deficiency Causes Anxiety-Like Behaviors in Mice.

Hai-Liang Yan,Cong Liu,Zhao-Qian Teng,Xiao-Wen Sun,Pei-Pei Liu,Zhi-Meng Wang,Hong-Zhen Du,Xuan-Cheng He,Ting-Wei Mi,Ying-Ying Wang,Chang-Mei Liu

doi:10.3389/fnmol.2019.00260

Abstract

Anxiety and depression are major public health concerns worldwide. Although genome-wide association studies have identified several genes robustly associated with susceptibility for these disorders, the molecular and cellular mechanisms associated with anxiety and depression is largely unknown. Reduction of microRNA-137 (miR-137) level has been implicated in the etiology of major depressive disorder. However, little is known about the in vivo impact of the loss of miR-137 on the biology of anxiety and depression. Here, we generated a forebrain-specific miR-137 knockout mouse line, and showed that miR-137 is critical for dendritic and synaptic growth in the forebrain. Mice with miR-137 loss-of-function exhibit anxiety-like behavior, and impaired spatial learning and memory. We then observe an elevated expression of EZH2 in the forebrain of miR-137 knockout mice, and provide direct evidence that knockdown of EZH2 can rescue anxious phenotypes associated with the loss of miR-137. Together our results suggest that loss of miR-137 contributes to the etiology of anxiety, and EZH2 might be a potential therapeutic target for anxiety and depressive phenotypes associated with the dysfunction of miR-137.

Highlights

Anxiety and depression are common mood disorders that affect millions of people irrespective of age, race, ethnicity and gender, resulting in the inability to concentrate, insomnia, feelings of extreme sadness and guilt, helplessness and hopelessness, and suicide attempt (WHO, 2012; Jesulola et al, 2018)
Despite continued research in neurophysiology and neuropsychiatry increasing the understanding of the pathophysiology of anxiety and depression, mechanisms associated with the pathogenesis of anxiety and depression have yet to be completely understood and current treatments remain ineffective in a large subset of patients (Brigitta, 2002; Menard et al, 2016; Jesulola et al, 2018)
We have previously found that partial loss of miR-137 in mice causes repetitive behavior and impairs sociability and learning via increased PDE10A, a cyclic nucleotide phosphodiesterase that is highly expressed in the brain (Cheng et al, 2018)

Summary

Introduction

Anxiety and depression are common mood disorders that affect millions of people irrespective of age, race, ethnicity and gender, resulting in the inability to concentrate, insomnia, feelings of extreme sadness and guilt, helplessness and hopelessness, and suicide attempt (WHO, 2012; Jesulola et al, 2018). Either overexpression or downregulation of miR-137 impairs brain function, suggesting miR-137-mediated regulation during neurodevelopment is dosage-dependent (Cheng et al, 2018). MiR-137 overexpression has been suggested to be associated with the etiology of schizophrenia (Guan et al, 2014). We have previously found that partial loss of miR-137 in mice causes repetitive behavior and impairs sociability and learning via increased PDE10A, a cyclic nucleotide phosphodiesterase that is highly expressed in the brain (Cheng et al, 2018). Loss of miR-137 in the brain leads to synaptic and dendritic overgrowth (Cheng et al, 2018)

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Conclusion