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

  • CNS Neurosci Ther. 2023 Jun 12. doi: 10.1111/cns.14291.
Xiaodong Wu  1  2  3 ,  Yulong Zhang  1  2  3 ,  Ping Wang  1  2  3 ,  Xiaohui Li  4 ,  Zhen Song  1  2  3 ,  Chuke Wei  1  2  3 ,  Qing Zhang  1  2  3 ,  Bei Luo  1  2  3 ,  Zhichun Liu  1  2  3 ,  Yingying Yang  1  2  3 ,  Zhenhua Ren  4 ,  Huanzhong Liu  1  2  3
Affiliations
  • 1. Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei, China.
  • 2. Department of Psychiatry, School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei, China.
  • 3. Department of Psychiatry, Anhui Psychiatric Center, Anhui Medical University, Hefei, China.
  • 4. Department of Anatomy, Anhui Medical University, Hefei, China.
PMID: 37308778 DOI: 10.1111/cns.14291
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.

Keywords
depression; miR-144-5p; neuroinflammation; neuronal destruction.
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