Targeting miR-124-3p to Induce Antidepressant-Like Effects in Female Mice: MicroRNA Modulation of Stress Resilience.

Authors

Maria A Kuznetsova, Alexandra Fraser, Ching-Seng Ang, Nicholas A Williamson, Nafisa Kazi, Anthony J Hannan, Thibault Renoir

Published in

The European journal of neuroscience. Volume 64. Issue 2. Pages e70634.

Abstract

MicroRNAs (miRNAs) play crucial roles in regulating gene expression and have been implicated in the pathophysiology of depression. Among them, miR-124-3p is one of the most abundant brain-enriched miRNAs and has emerged as a potential therapeutic target for mood disorders. This study aimed to evaluate the antidepressant-like effects of an acute administration of miR-124-3p and to identify associated molecular and neuronal changes across key brain regions. Female C57BL/6 mice received intracerebroventricular injections of a miR-124-3p mimic or a control oligonucleotide. Affective-like behavioural responses were assessed using the Porsolt swim test (PST) and the light-dark box test (LDB). Proteomic alterations in the hippocampus, hypothalamus and prefrontal cortex were analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and stress-related neuronal activity was evaluated using c-Fos immunofluorescence. Mice treated with the miR-124-3p mimic exhibited reduced immobility in the PST, indicative of an antidepressant-like effect and enhanced active stress coping. Proteomic profiling revealed region-specific changes, including downregulation of immune- and stress-related proteins in the hypothalamus and hippocampus, and upregulation of synaptic and metabolic proteins in the prefrontal cortex. c-Fos analyses showed decreased stress-induced neuronal activation in the hypothalamic paraventricular and periventricular nuclei, alongside increased activity in the hippocampal dentate gyrus. Collectively, these findings suggest that miR-124-3p mimic treatment is associated with antidepressant-like effects by reducing neuroimmune activation and enhancing neuronal plasticity. Our results support a model in which miR-124-3p promotes stress resilience through coordinated modulation of inflammatory and plasticity-related processes across distinct brain circuits.

PMID:
42472993
Bibliographic data and abstract were imported from PubMed on 20 Jul 2026.

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