One‐hertz low‐frequency stimulation of anterior substantia nigra pars reticulata attenuates seizure via biased disinhibitory circuits

Abstract Objective Low‐frequency stimulation (LFS) targeting key seizure nodes holds promising potential for the treatment of epilepsy. The substantia nigra pars reticulata (SNr) plays an important role in seizure control yet has structural heterogeneity. This study aims to explore the therapeutic potential of LFS across different subregions of the SNr. Methods Different types of seizure models, including kainic acid‐induced hippocampal and neocortical seizure models and a pentetrazol‐induced seizure model, were used to address the therapeutic potential of LFS in different subregions of SNr. Fiber photometry, specific cell ablation, and viral tracing were used to measure the release of different neurotransmitters and heterogeneous circuit organizations of subregions of SNr. Results We found that 1‐Hz LFS in the anterior SNr (a‐SNr), but not in the posterior SNr (p‐SNr), generally alleviated seizure severity in all three mouse seizure models. Notably, the antiseizure effects were frequency‐dependent, with 100‐Hz high‐frequency stimulation being less effective and 20‐Hz stimulation having hardly any impact. Regarding the mechanism of the discrepancy, fiber photometry showed that 1‐Hz, rather than 20‐ or 100‐Hz, stimulation in the a‐SNr significantly increased γ‐aminobutyric acid release from exogenous inputs compared with stimulation in the p‐SNr, which was further supported by their biased brain‐wide disinhibitory inputs. Significance These results demonstrate that 1‐Hz LFS in the a‐SNr may be of therapeutic significance in various types of seizures, highlighting the necessity to precisely target the a‐SNr at low frequency for seizure treatment.