Hippocampus chronic deep brain stimulation induces reversible transcript changes in a macaque model of mesial temporal lobe epilepsy

Background: Deep brain stimulation (DBS) has seizure-suppressing effects but the molecular mechanisms underlying its therapeutic action remain unclear. This study aimed to systematically elucidate the mechanisms underlying DBS-induced seizure suppression at a molecular level. Methods: We established a macaque model of mesial temporal lobe epilepsy (mTLE), and continuous high-frequency hippocampus DBS (hip-DBS) was applied for 3 months. The effects of hip-DBS on hippocampus gene expression were examined using high-throughput microarray analysis followed by bioinformatics analysis. Moreover, the microarray results were validated using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analyses. Results: The results showed that chronic hip-DBS modulated the hippocampal gene expression. We identified 4119 differentially expressed genes and assigned these genes to 16 model profiles. Series test of cluster analysis showed that profiles 5, 3, and 2 were the predominant expression profiles. Moreover, profile 5 was mainly involved in focal adhesion and extracellular matrix-receptor interaction pathway. Nine dysregulated genes (Arhgap5, Col1a2, Itgb1, Pik3r1, Lama4, Fn1, Col3a1, Itga9, and Shc4) and three genes (Col1a2, Itgb1, and Flna) in these two pathways were further validated by qRT-PCR and Western blot analyses, respectively, which showed a concordance. Conclusion: Our findings suggest that hip-DBS could markedly reverse mTLE-induced abnormal gene expression. Findings from this study establish the basis for further investigation of the underlying regulatory mechanisms of DBS for mTLE.

Automated summary

This study systematically elucidated the molecular mechanisms underlying seizure suppression induced by hip-DBS in a macaque model of mTLE. Chronic hip-DBS modulated hippocampal gene expression, affecting pathways related to focal adhesion and extracellular matrix-receptor interaction. The findings suggest that hip-DBS could reverse abnormal gene expression in mTLE and lay the groundwork for further investigation into the regulatory mechanisms of DBS for this condition.