MiR-30a-5p mediates epileptogenesis in epilepsy models by targeting SOX4 to regulate the Wnt/β-catenin pathway.

Abstract

Objective: The pathogenesis of epilepsy is closely associated with neuronal synaptic plasticity. MicroRNAs (miRNAs) can regulate various biological processes by binding to specific sequences on target genes. This study employs bioinformatics, molecular dynamics, and experimental approaches to investigate the mechanism by which MiR-30a-5p treats epilepsy through targeting SOX4 and regulating the Wnt/β-catenin signaling pathway.

Methods: Performed bioinformatics analysis to predict the signaling pathways involved in miRNA-30a-5p-mediated intervention in epilepsy. RT-qPCR was used to detect the expression levels of miR-30a-5p in the hippocampal tissues of epileptic rats and in primary hippocampal neurons subjected to Mg²⁺-free treatment. The effects of miR-30a-5p inhibition on synaptic plasticity were assessed using EEG, the Morris water maze test, Golgi staining, Sholl analysis, and Western blotting. TargetScan and miRTarBase were employed to predict the target genes of miR-30a-5p. The interaction was validated through dual-luciferase reporter assays, IHC, IF, and Western blotting, and the effect of SOX4 inhibition on synaptic plasticity was evaluated. The involvement of the Wnt signaling pathway was assessed by Western blotting.

Results: The expression level of miR-30a-5p was significantly elevated in the hippocampal region of epileptic rats and in magnesium-depleted hippocampal neuronal cultures. SOX4 was identified as a direct target of miR-30a-5p. Inhibiting miR-30a-5p reduces the expression of synapse-associated proteins (SYP/CaMKII/PSD95), while upregulating SOX4 and downregulating the levels of Wnt3a, β-catenin, and cyclin D1. miR-30a-5p may participate in alterations of neuronal synaptic plasticity by directly targeting and inhibiting SOX4 expression, thereby activating the Wnt/β-catenin signaling pathway.

Significance: This study provides evidence that miR-30a-5p participates in the process of synaptic plasticity impairment in epileptic neurons. The study confirms a direct interaction between miR-30a-5p and SOX4. Furthermore, miR-30a-5p regulates the Wnt/β-catenin signaling pathway by targeting SOX4, thereby influencing neuronal synaptic plasticity impairment. This discovery provides a novel potential therapeutic target for delaying epilepsy progression.

Plain language summary: Epilepsy is a common brain disorder that affects millions of people worldwide. This study found that a small molecule called miR-30a-5p increases in the brain during epilepsy and disrupts normal communication between neurons. By blocking this molecule in laboratory experiments, we were able to improve neuron function and reduce damage. These findings suggest that targeting miR-30a-5p could lead to new treatments to slow down the progression of epilepsy.