Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei, China.
Department of Psychiatry, School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei, China.
CNS Neurosci Ther. 2023 Nov;29(11):3598-3611. doi: 10.1111/cns.14291. Epub 2023 Jun 12.
Neuronal abnormalities are closely associated with major depressive disorder (MDD). Available evidence suggests a role for microRNAs (miRNAs) in regulating the expression of genes involved in MDD. Hence, miRNAs that can be potential therapeutic targets need to be identified.
A mouse model of chronic unpredictable stress (CUS) was used to evaluate the function of miRNAs in MDD. miR-144-5p was screened from the hippocampi of CUS mice based on sequencing results. Adenovirus-associated vectors were used to overexpress or knockdown miR-144-5p in mice. BpV(pic) and LY294002 were used to determine the relationship between miR-144-5p target genes PTEN and TLR4 in neuronal impairment caused by miR-144-5p deficiency. Western blotting, immunofluorescence, ELISA immunosorbent assay, and Golgi staining were used to detect neuronal abnormalities. Serum samples from healthy individuals and patients with MDD were used to detect miR-144-5p levels in the serum and serum exosomes using qRT-PCR.
miR-144-5p expression was significantly decreased within the hippocampal dentate gyrus (DG) of CUS mice. Upregulation of miR-144-5p in the DG ameliorated depression-like behavior in CUS mice and attenuated neuronal abnormalities by directly targeting PTEN and TLR4 expression. Furthermore, miR-144-5p knockdown in normal mice led to depression-like behavior via inducing neuronal abnormalities, including abnormal neurogenesis, neuronal apoptosis, altered synaptic plasticity, and neuroinflammation. miR-144-5p deficiency-mediated neuronal impairment was mediated by PI3K/Akt/FoxO1 signaling. Furthermore, miR-144-5p levels were downregulated in the sera of patients with MDD and associated with depressive symptoms. Consistently, serum exosome-derived miR-144-5p levels were decreased in patients with MDD.
miR-144-5p plays a vital role in regulating neuronal abnormalities in depression. Our findings provide translational evidence that miR-144-5p is a new potential therapeutic target for MDD.
神经元异常与重度抑郁症（MDD）密切相关。现有证据表明 microRNAs（miRNAs）在调节 MDD 相关基因的表达中起作用。因此，需要确定可以作为潜在治疗靶点的 miRNAs。
采用慢性不可预测应激（CUS）小鼠模型来评估 miRNAs 在 MDD 中的功能。根据测序结果，从 CUS 小鼠海马中筛选出 miR-144-5p。使用腺相关病毒载体在小鼠中过表达或敲低 miR-144-5p。BpV(pic)和 LY294002 用于确定 miR-144-5p 缺陷引起的神经元损伤中 miR-144-5p 靶基因 PTEN 和 TLR4 之间的关系。Western blot、免疫荧光、ELISA 免疫吸附测定和高尔基染色用于检测神经元异常。使用 qRT-PCR 检测健康个体和 MDD 患者的血清样本中的血清和血清外泌体中的 miR-144-5p 水平。
CUS 小鼠海马齿状回（DG）中 miR-144-5p 的表达显著降低。DG 中 miR-144-5p 的上调改善了 CUS 小鼠的抑郁样行为，并通过直接靶向 PTEN 和 TLR4 表达减轻了神经元异常。此外，正常小鼠中 miR-144-5p 的敲低通过诱导神经元异常导致抑郁样行为，包括异常神经发生、神经元凋亡、改变的突触可塑性和神经炎症。miR-144-5p 缺陷介导的神经元损伤是通过 PI3K/Akt/FoxO1 信号传导介导的。此外，MDD 患者的血清中 miR-144-5p 水平下调，并与抑郁症状相关。一致地，MDD 患者的血清外泌体衍生的 miR-144-5p 水平降低。
miR-144-5p 在调节抑郁中的神经元异常中起关键作用。我们的研究结果提供了转化证据，表明 miR-144-5p 是 MDD 的一个新的潜在治疗靶点。
