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

Abstract Objective The piriform cortex (PC) plays a critical role in ictogenesis, where an excitation/inhibition imbalance contributes to epilepsy etiology. However, the epileptic dynamics of the gamma‐aminobutyric acid (GABA) system and the precise role of GABAergic neurons within the PC in epilepsy remain unclear. Methods We combined Ca 2+ 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. Results GABAergic system dynamics in the PC were bidirectional and asymmetric, accompanied by PC optokindling‐induced seizures, notably characterized by a robust response of Gad2 neurons but a rapid descent of GABA content during seizures. Chemogenetic inhibition of PC Gad2 neurons induced seizure‐like behavior, with a discrepancy between the GABAergic neuron activities and GABA levels, signifying a transition from interictal to ictal states. Surprisingly, selective inhibition of Gad2 neurons in the PC produced paradoxical activation in a subset of Gad2 neurons. Moreover, the chronic deficiency of PC Gad2 neurons triggered spontaneous recurrent seizures. Significance Our findings uncover the dynamic interplay within PC inhibitory components and elaborate counteractive mechanisms in seizure regulation. These insights could inform future therapeutic strategies targeting GABAergic neurons to control epileptic activity.