biostudies-literaturePalmer DNational Institute of Neurological Disorders and StrokeNINDS NIH HHS966-978https://www.ebi.ac.uk/biostudies/studies/S-EPMC12927675biostudies-literatureUnknown67(2)<h4>Objective</h4>For over four decades, the substantia nigra pars reticulata (SNr) has been recognized as a critical structure in the modulation of seizure activity. Pharmacological and optogenetic inhibition of the SNr produces robust seizure suppression in a range of seizure models. These findings have given rise to a longstanding, yet unresolved question: do seizures involve a failure of inhibition within the SNr?<h4>Methods</h4>We recorded single-unit activity in the SNr during spike-and-wave discharges (SWDs) in male and female WAG/Rij rats, a model of genetic absence epilepsy. We monitored extracellular γ-aminobutyric acid (GABA) levels using intensity-based GABA sensing fluorescence reporter (iGABASnFR). To emphasize the multi-modal efficacy of SNr inhibition on seizure suppression, we optogenetically inhibited the SNr.<h4>Results</h4>Fifty percent of recorded neurons exhibited a marked increase in firing at SWD onset, with activity returning to baseline at SWD termination. Extracellular GABA levels revealed a decrease in fluorescence during SWDs, consistent with reduced GABAergic transmission. Optogenetic inhibition of SNr neurons using continuous (open-loop) inhibition, but not closed-loop (responsive) inhibition, significantly reduced SWD incidence.<h4>Significance</h4>These data suggest that a loss of GABAergic input to the SNr is associated with increased neuronal activity. Optogenetically restoring inhibition effectively reduced seizure burden. Together, these findings address a long-standing gap in the literature and provide compelling evidence that impaired inhibition within the SNr contributes to seizure expression.EpilepsiaRestoring failed inhibition in the substantia nigra pars reticulata suppresses absence seizures in rats.PMC12927675T32NS041218R01NS097762Forcelli PAPalmer DfalseRestoring failed inhibition in the substantia nigra pars reticulata suppresses absence seizures in rats.<h4>Objective</h4>For over four decades, the substantia nigra pars reticulata (SNr) has been recognized as a critical structure in the modulation of seizure activity. Pharmacological and optogenetic inhibition of the SNr produces robust seizure suppression in a range of seizure models. These findings have given rise to a longstanding, yet unresolved question: do seizures involve a failure of inhibition within the SNr?<h4>Methods</h4>We recorded single-unit activity in the SNr during spike-and-wave discharges (SWDs) in male and female WAG/Rij rats, a model of genetic absence epilepsy. We monitored extracellular γ-aminobutyric acid (GABA) levels using intensity-based GABA sensing fluorescence reporter (iGABASnFR). To emphasize the multi-modal efficacy of SNr inhibition on seizure suppression, we optogenetically inhibited the SNr.<h4>Results</h4>Fifty percent of recorded neurons exhibited a marked increase in firing at SWD onset, with activity returning to baseline at SWD termination. Extracellular GABA levels revealed a decrease in fluorescence during SWDs, consistent with reduced GABAergic transmission. Optogenetic inhibition of SNr neurons using continuous (open-loop) inhibition, but not closed-loop (responsive) inhibition, significantly reduced SWD incidence.<h4>Significance</h4>These data suggest that a loss of GABAergic input to the SNr is associated with increased neuronal activity. Optogenetically restoring inhibition effectively reduced seizure burden. Together, these findings address a long-standing gap in the literature and provide compelling evidence that impaired inhibition within the SNr contributes to seizure expression.2026-01-01T00:00:00Z2026 Feb2026-07-09T12:14:45.688Z2026-07-09T11:14:58.584ZS-EPMC129276754118251010.1111/epi.18701