MAD2B Blunts Chronic Unpredictable Stress and Corticosterone Stimulation-Induced Depression-Like Behaviors in Mice.
MAD2B Blunts Chronic Unpredictable Stress and Corticosterone Stimulation-Induced Depression-Like Behaviors in Mice.
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DOI：
10.1093/ijnp/pyac083
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发表时间：
2023-02-14
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抑郁症是一种常见的复发性精神疾病。异常的神经结构和活动在抑郁症的发生中起着基础性作用。有丝分裂阻滞缺陷蛋白（MAD 2B）在神经元中高度表达，并可能与中枢神经系统的突触可塑性有关。然而，MAD 2B在抑郁症中的作用以及相关的分子机制尚不确定。在这里，我们采用慢性不可预测的压力暴露或皮质酮（CORT）刺激诱导的抑郁症小鼠模型。通过蔗糖偏好、强迫游泳和悬尾试验评价小鼠的抑郁样行为。海马MAD 2B的过表达由含有增强型绿色荧光蛋白的腺相关病毒8介导。从大鼠胚胎海马获得体外原代神经元细胞，并用CORT处理，并使用慢病毒进行MAD 2B过表达。MAD 2B和谷氨酸代谢型受体4（GRM 4）水平通过蛋白质印迹和定量PCR进行评估。通过定量PCR检测原代神经元miR-29 b-3 p的表达。在表现出抑郁样行为的小鼠中，MAD 2B表达在海马中减少。然而，海马MAD 2B过表达保护小鼠免受慢性不可预测的应激或CORT诱导的抑郁样行为的影响，这种影响与GRM 4表达减少有关，GRM 4是一种参与抑郁症的突触前受体。此外，MAD 2B在原代神经元细胞中的过表达也降低了GRM 4的表达，同时提高了miR-29 b-3 p的水平;在CORT刺激下也观察到了这种现象。我们的研究结果表明，神经元MAD 2B通过miR-29 b-3 p/GRM 4信号通路在抑郁症的发病机制中发挥重要作用。MAD 2B可能是抑郁症潜在的治疗靶点。
Depression is a prevalent and recurrent psychiatric disorder. Aberrant neural structure and activity play fundamental roles in the occurrence of depression. Mitotic arrest deficient protein (MAD2B) is highly expressed in neurons and may be implicated in synaptic plasticity in the central nervous system. However, the effect of MAD2B in depression, as well as the related molecular mechanism, is uncertain. Here, we employed mouse models of depression induced by chronic unpredictable stress exposure or corticosterone (CORT) stimulation. Depression-like behaviors in mice were evaluated by sucrose preference, forced swimming, and tail suspension tests. Hippocampal MAD2B overexpression was mediated by adeno-associated virus 8 containing enhanced green fluorescent protein. In vitro primary neuronal cells were obtained from the hippocampus of rat embryos and were treated with CORT, and MAD2B overexpression was performed using lentivirus. MAD2B and glutamate metabotropic receptor 4 (GRM4) levels were evaluated by western blots and quantitative PCR. Primary neuronal miR-29b-3p expression was detected by quantitative PCR. MAD2B expression was reduced in the hippocampus in mice exhibiting depressive-like behaviors. However, hippocampal MAD2B overexpression protected mice from developing either chronic unpredictable stress– or CORT-induced depression-like behaviors, an effect associated with reduced expression of GRM4, a presynaptic receptor involved in depression. Moreover, MAD2B overexpression in primary neuronal cells also decreased GRM4 expression while enhancing the level of miR-29b-3p; this phenomenon was also observed under CORT stimulation. Our results suggest an important role of neuronal MAD2B in the pathogenesis of depression via the miR-29b-3p/GRM4 signaling pathway. MAD2B could be a potential therapeutic target for depressive disorders.
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