REST/NRSF Regulation of Epilepsy and Cognitive Impairment: Mechanisms and EEG Correlations

This study aimed to investigate the relationship between REST/NRSF and cognitive impairment in epilepsy, focusing on EEG alterations and serum REST/NRSF levels as potential biomarkers. Additionally, the study explored how REST/NRSF regulation in the hippocampus affects epileptic activity and cognitive function through the modulation of Kv7.2/7.3 potassium channels. We studied 50 epilepsy patients (25 with cognitive impairment, 25 without) and 40 healthy controls. High-density EEG was used to assess brain activity across various frequency bands. Serum REST/NRSF levels were measured by ELISA and correlated with cognitive performance (MoCA). ROC analysis and logistic regression assessed the predictive value of EEG and REST/NRSF for cognitive dysfunction. In animal models, KA-induced epileptic mice were used to study REST/NRSF expression and its effect on Kv7.2/7.3 channels through Western blotting and qRT-PCR. The δ relative power and DTABR in the left frontoparietal, left frontotemporal, and left temporal regions of the epilepsy cognitive impairment group were significantly higher than those of the non-cognitive impairment and control groups (P < 0.05); conversely, the α relative power in the same regions was significantly lower (P < 0.05). Serum REST/NRSF levels were significantly higher in the cognitive impairment group and negatively correlated with cognitive function (P < 0.05). ROC curve analysis revealed high predictive value for δ and α frequency band power and serum REST/NRSF levels for cognitive dysfunction in epilepsy (AUC > 0.8). In KA model mice, REST/NRSF protein levels were significantly elevated in the hippocampal CA1 region, while Kv7.2/7.3 expression was reduced. Knockdown of REST/NRSF in the hippocampus resulted in reduced seizure severity, while overexpression of REST/NRSF exacerbated seizures. This study demonstrates that cognitive impairment in epilepsy is linked to changes in EEG power spectra and elevated serum REST/NRSF levels. These findings suggest that REST/NRSF plays a role in regulating both epileptic activity and cognitive dysfunction, potentially through modulation of Kv7.2/7.3 potassium channels. These results highlight REST/NRSF as a promising biomarker and therapeutic target for cognitive impairment in epilepsy.