1. Academic Validation
  2. Hippocampal microRNA-26a-3p deficit contributes to neuroinflammation and behavioral disorders via p38 MAPK signaling pathway in rats

Hippocampal microRNA-26a-3p deficit contributes to neuroinflammation and behavioral disorders via p38 MAPK signaling pathway in rats

  • J Neuroinflammation. 2022 Nov 24;19(1):283. doi: 10.1186/s12974-022-02645-1.
Changmin Wang 1 Ye Li 1 Yuhang Yi 1 Guiyu Liu 1 Ruojing Guo 1 Liyan Wang 2 Tian Lan 1 Wenjing Wang 1 Xiao Chen 1 Shihong Chen 3 Shu Yan Yu 4 5
Affiliations

Affiliations

  • 1 Department of Physiology, Shandong University, School of Basic Medical Sciences, 44 Wenhuaxilu Road, Jinan, 250012, Shandong, People's Republic of China.
  • 2 Morphological Experimental Center, Shandong University, School of Basic Medical Sciences, 44 Wenhuaxilu Road, Jinan, 250012, Shandong, People's Republic of China.
  • 3 Department of Endocrinology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, 250033, Shandong, People's Republic of China. [email protected].
  • 4 Department of Physiology, Shandong University, School of Basic Medical Sciences, 44 Wenhuaxilu Road, Jinan, 250012, Shandong, People's Republic of China. [email protected].
  • 5 Shandong Provincial Key Laboratory of Mental Disorders, School of Basic Medical Sciences, 44 Wenhuaxilu Road, Jinan, 250012, Shandong, People's Republic of China. [email protected].
Abstract

Background: Neuronal injury is considered a critical risk factor in the pathogenesis of most neurological and neuropsychiatric diseases. However, the underlying molecular mechanisms and identification of potential therapeutic targets for preventing neuronal injury associated with brain function remain largely uncharacterized. Therefore, identifying neural mechanisms would put new insights into the progression of this condition and provide novel therapeutic strategies for the treatment of these diseases.

Methods: Stereotactic injection of AAV virus was used to knock-down the miR-26a-3p within hippocampus of rats. Behavioral changes was detected by open field test (OFT), elevated plus maze (EPM), forced swim test (FST) and sucrose preference test (SPT). The inflammatory cytokines and related proteins were verified by real-time quantitative PCR, immunoblotting or immunofluorescence assay. Golgi staining and electron microscopy analysis was used to observe the dendritic spine, synapse and ultrastructural pathology. SB203580 (0.5 mg/kg) were administered daily to prevent p38 MAPK via an intraperitoneal (i.p.) injection. Finally, electrophysiological method was used to examine the synaptic transmission via whole-cell patch-clamp recording.

Results: Here, we showed that miR-26a-3p deficiency within hippocampal regions leads to the activation of microglia, increased level of pro-inflammatory cytokines and behavioral disorders in rats, effects which appear to be mediated by directly targeting the p38 mitogen-activated protein kinase (MAPK)-NF-κB signaling pathway. Specifically, we found that the enhanced glia-activation may consequently result in neuronal deterioration that mainly presented as the dysregulation of structural and functional plasticity in hippocampal neurons. In contrast, preventing p38 pathway by SB203580 significantly ameliorated abnormal behavioral phenotypes and neuronal jury resulting from miR-26a-3p knock-down.

Conclusion: These results suggest that the normal expression of miR-26a-3p exerts neuroprotective effects via suppressing neural abnormality and maintaining neuroplasticity to against behavioral disorders in rats. These effects appear to involve a down-regulation of p38 MAPK-NF-κB signaling within the hippocampal region. Taken together, these findings provide evidence that miR-26a-3p can function as a critical factor in regulating neural activity and suggest that the maintaining of normal structure and function of neurons might be a potential therapeutic strategy in the treatment of neurological disorders.

Keywords

Behavioral disorder; MicroRNA-26a-3p; Neuroinflammation; Neuroplasticity; p38 MAPK.

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