Depolarization block paradoxically drives surges of neurotransmitter release during seizure activity

Abstract Objective This study was undertaken to investigate the mechanisms underlying the paradoxical phenomena of excessive neurotransmitter release and suppressed sodium‐spike generation due to depolarization block (DB) during seizure activity. Methods We employed acute neocortical slices from mice to investigate DB in pyramidal cells (PCs) during epileptiform activity (EA). Local high‐K + puff was applied to induce DB and monitor glutamate and dopamine release. Additionally, we examined dopamine release in the neocortex during kindling‐evoked seizures following acute lesions of dopaminergic axons in the medial forebrain bundle in vivo. Results Membrane potential levels of DB in PCs during EA remained constant even with strong hyperpolarization, suggesting dependence on an ionic reversal potential. Local high‐K + puff induced DB in both PC soma and axons, accompanied by glutamate release. Surprisingly, dopamine release in neocortical slices (lacking dopaminergic cell bodies) was also induced by high‐K + puff or during EA. In animals with bilateral medial forebrain bundle lesions, dopamine release in neocortex was largely preserved during kindling‐evoked seizures. Significance Our findings demonstrate that, during epileptiform activity, DB is predominantly determined by excessive accumulation of extracellular K + , and that axonal rather than somatic DB causes aberrant synaptic transmission. Local extracellular K + rises and subsequent axonal DB may trigger neurotransmitter surges during epileptic seizures, providing a novel mechanistic insight into seizure‐related neurotransmitter dynamics and a possible explanation for severe epilepsy‐associated neuropsychiatric comorbidities.