Spautin-1 alleviates depression-like behaviors in mice after traumatic brain injury by inhibiting MMP3 expression in microglia in the Hippocampal CA1 region

Background

Although the treatment of depressive symptoms after traumatic brain injury (TBI) remains challenging, the underlying neurological mechanisms remain poorly understood. This study investigated the potential role of Spautin-1 in mitigating depression-like behaviors in mice following TBI by inhibiting matrix metalloproteinase-3 (MMP3) expression in microglial within the CA1 region of the hippocampus. The findings demonstrated that Spautin-1 treatment significantly reduced MMP3 expression and microglial activation, which led to an improvement in depression-like behaviors. This suggests that targeting MMP3 in microglia may offer a novel therapeutic approach for managing post-TBI depressive symptoms.

Methods

Mild TBI was induced in mice using the Feeney weight-drop paradigm after the immediate administration of Spautin-1 into the left lateral ventricle. Behavioral and pathological changes were assessed at various time points post-injury using neurological severity scores (NSS), the forced swim test (FST), the tail suspension test (TST), and the social interaction test (SI) task. Molecular and structural alterations were analyzed through transcriptomic analysis, real-time quantitative PCR, electron microscopy, local field potential (LFP) recordings, and immunofluorescence staining.

Results

Mild TBI reduced in the SI index, increased immobility time in behavioral tests, and exacerbated microinjury, as indicated by the upregulation of Iba1, GFAP, and MMP3-positive, USP13-positive, and Beclin-1-positive microglia. Quantitative polymerase chain reaction (qPCR) analysis showed that MMP3 expression was significantly increased after TBI. Notably, Spautin-1 administration effectively reversed these pathological and functional deficits: it reduced the intensity of MMP3 by 63.4 %, decreased the intensity of Iba1 by 33.5 %, improved the ratio of social interaction by 36.7 %, and lessened the immobility time in TST by 26.2 % as well as the immobility time in SI by 33.9 %. Additionally, TBI resulted in the accumulation of autophagic vacuoles and abnormal organelles. Functional impairments in the CA1 region were observed, including weakened δ-γ and θ-γ phase coupling, reduced expression of c-Fos-positive GAD2 and VGLUT1, decreased MAP2 levels, and diminished δ and θ oscillatory power.

Conclusions

Spautin-1 alleviates depression-like behaviors in mice following mild TBI by inhibiting the MMP3 signaling pathway in microglia within the CA1 region of the hippocampus, indicating a potential therapeutic strategy for addressing post-TBI depression.