Related Experiment Video
Updated: Oct 13, 2025
Author Spotlight: Induced Microglia-Like Cell Technology to Shed Light on the Role of Microglial Dysfunction in Neuropsychiatric Disorders
Published on: September 6, 2024
Microglia secrete miR-146a-5p-containing exosomes to regulate neurogenesis in depression
Cuiqin Fan1, Ye Li1, Tian Lan1
1Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Abstract:
Enhancing neurogenesis within the hippocampal dentate gyrus (DG) is critical for maintaining brain development and function in many neurological diseases. However, the neural mechanisms underlying neurogenesis in depression remain unclear. Here, we show that microglia transfer a microglia-enriched microRNA, miR-146a-5p, via secreting exosomes to inhibit neurogenesis in depression. Overexpression of miR-146a-5p in hippocampal DG suppresses neurogenesis and spontaneous discharge of excitatory neurons by directly targeting Krüppel-like factor 4 (KLF4). Downregulation of miR-146a-5p expression ameliorates adult neurogenesis deficits in DG regions and depression-like behaviors in rats. Intriguingly, circular RNA ANKS1B acts as a miRNA sequester for miR-146a-5p to mediate post-transcriptional regulation of KLF4 expression. Collectively, these results indicate that miR-146a-5p can function as a critical factor regulating neurogenesis under conditions of pathological processes resulting from depression and suggest that microglial exosomes generate new crosstalk channels between glial cells and neurons.
Insights
Microglia release miR-146a-5p in exosomes to inhibit hippocampal neurogenesis in depression. Reducing this microRNA (miRNA) improves neurogenesis and depression-like behaviors, revealing a novel glial-neuronal communication pathway.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Neurogenesis in the hippocampal dentate gyrus (DG) is vital for brain function and affected in neurological diseases.
- Neural mechanisms of neurogenesis impairment in depression are not fully understood.
Purpose of the Study:
- To elucidate the role of microglia-derived microRNA-146a-5p (miR-146a-5p) in regulating hippocampal neurogenesis during depression.
- To identify the molecular targets and pathways involved in miR-146a-5p-mediated neurogenesis inhibition.
Main Methods:
- Investigated microglial exosome secretion of miR-146a-5p.
- Assessed the impact of miR-146a-5p overexpression and downregulation on neurogenesis and neuronal activity in the DG.
- Identified Krüppel-like factor 4 (KLF4) as a direct target of miR-146a-5p.
- Examined the regulatory role of circular RNA ANKS1B in mediating miR-146a-5p activity.
Main Results:
- Microglia transfer miR-146a-5p via exosomes, inhibiting DG neurogenesis in depression.
- Overexpression of miR-146a-5p in the DG suppresses neurogenesis and excitatory neuron discharge by targeting KLF4.
- Downregulation of miR-146a-5p reversed neurogenesis deficits and depression-like behaviors in rats.
- Circular RNA ANKS1B sequesters miR-146a-5p, affecting KLF4 expression.
Conclusions:
- miR-146a-5p is a critical regulator of neurogenesis in depression, acting through microglial exosomes.
- This study reveals a novel crosstalk mechanism between glial cells and neurons involving exosomal miRNAs.
- Targeting miR-146a-5p or related pathways may offer therapeutic strategies for depression-related neurogenesis deficits.
