Clinical and preclinical evaluation of miR‐144‐5p as a key target for major depressive disorder

Abstract Background 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. Methods 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. Results 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. Conclusion 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.