Asymmetric dynamics of GABAergic system and paradoxical responses of GABAergic neurons in piriform seizures

The piriform cortex (PC) plays a critical role in epileptogenesis, where an excitation/inhibition imbalance contributes to epilepsy etiology. However, the epileptic dynamics of the GABA system and the precise role of GABAergic neurons within the PC in epilepsy remain unclear. Here, we combined Ca2+ and GABA sensors to investigate the dynamics of Gad2-expressing neurons and GABA levels, and selectively manipulated GABAergic neurons in the PC through chemogenetic inhibition and caspase3-mediated apoptosis targeting Gad2 interneurons. The chronic deficiency of PC Gad2 neurons triggered spontaneous recurrent seizures. These findings uncover the dynamic interplay within PC inhibitory components and elaborate counteractive mechanisms in seizure regulation. To delve into the epileptic pathological features underlying this knock-down model, we conducted bulk RNA-seq on PC samples with Gad2 neuron loss in the transcriptome. We employed a knock-down strategy using genetically engineered caspase3, which triggers apoptosis upon activation. Cre-dependent caspase3 was injected to specifically target and eliminate Gad2-positive neurons in the PC.