Neocortical GABA release at high intracellular sodium and low extracellular calcium: an anti‐seizure mechanism

In epilepsy, the GABA and glutamate balance may be disrupted and a transient decrease in extracellular calcium occurs before and during a seizure. Flow Cytometry based fluorescence activated particle sorting experiments quantified synaptosomes from human neocortical tissue, from both epileptic and non‐epileptic patients (27.7% vs. 36.9% GABAergic synaptosomes, respectively). Transporter‐mediated release of GABA in human and rat neocortical synaptosomes was measured using the superfusion technique for the measurement of endogenous GABA. GABA release was evoked by either a sodium channel activator or a sodium/potassium‐ATPase inhibitor when exocytosis was possible or prevented, and when the sodium/calcium exchanger was active or inhibited. The transporter‐mediated release of GABA is because of elevated intracellular sodium. A reduction in the extracellular calcium increased this release (in both non‐epileptic and epileptic, except Rasmussen encephalitis, synaptosomes). The inverse was seen during calcium doubling. In humans, GABA release was not affected by exocytosis inhibition, that is, it was solely transporter‐mediated. However, in rat synaptosomes, an increase in GABA release at zero calcium was only exhibited when the exocytosis was prevented. The absence of calcium amplified the sodium/calcium exchanger activity, leading to elevated intracellular sodium, which, together with the stimulation‐evoked intracellular sodium increment, enhanced GABA transporter reversal. Sodium/calcium exchange inhibitors diminished GABA release. Thus, an important seizure‐induced extracellular calcium reduction might trigger a transporter‐ and sodium/calcium exchanger‐related anti‐seizure mechanism by augmenting transporter‐mediated GABA release, a mechanism absent in rats. Uniquely, the additional increase in GABA release because of calcium‐withdrawal dwindled during the course of illness in Rasmussen encephalitis. Seizures cause high Na+ influx through action potentials. A transient decrease in [Ca2+]e (seizure condition) increases GABA transporter (GAT)‐mediated GABA release because of elevated [Na+]i. This amplifies the Sodium‐Calcium‐Exchanger (NCX) activity, further increasing [Na+]i and GABA release. The reduction in [Ca2+]e triggers a GAT‐NCX related anti‐seizure mechanism by augmenting GAT‐mediated GABA release. This mechanism, obvious in humans, is absent in rats. Seizures cause high Na+ influx through action potentials. A transient decrease in [Ca2+]e (seizure co