Bicarbonate Efflux induces GABAergic Excitation and Seizures through pH Regulation

Abstract

GABAergic signaling can paradoxically excite neurons and initiate seizures, but the underlying mechanisms remain unclear. We developed a computational model integrating pH regulation into neural dynamics to investigate GABAergic excitation. Our results show that GABA-induced bicarbonate efflux causes intracellular acidification and charge accumulation, which enhances neuronal excitability and can trigger seizure-like discharges through bifurcations in the neurodynamic system. Furthermore, we demonstrate that active pH-regulating transporters effectively counteract GABA-induced acidification to maintain neural stability. This work elucidates a novel pH-regulating mechanism for excitatory GABA responses, explaining how impaired pH regulation or excessive GABA stimulation may predispose neurons to seizures and suggesting new therapeutic targets for epilepsy.