Cellular mechanisms underlying spontaneous interictal spikes in an acute model of focal cortical epileptogenesis.

The cellular mechanisms involved in the generation of spontaneous epileptiform potentials were investigated in the pirifom cortex of the in vitro isolated guinea-pig brain. A single, unilateral injection of bicuculline (150-200 nmol) in the anterior piriform cortex induced locally spontaneous interictal spikes that recurred with a period of 8.81+/-4.47 s and propagated caudally to the ipsi- and contralateral hemispheres. Simultaneous extra- and intracellular recordings from layer II and III principal cells showed that the spontaneous interictal spike correlates to a burst of action potentials followed by a large afterdepolarization. Intracellular application of the sodium conductance blocker, QX-314 (80 mM), abolished bursting activity and unmasked a high-threshold slow spike enhanced by the calcium chelator EGTA (50 mM). The slow spike was abolished by membrane hyperpolarization and by local perfusion with 2 mM cadmium. The depolarizing potential that followed the primary burst was reduced by arterial perfusion with the N-methyl-D-aspartate receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (100-200 microM). The non-N-methyl-D-aspartate glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (20 microM), completely and reversibly blocked the spontaneous spikes. The interictal spikes were terminated by a large afterpotential blocked either by intracellular QX-314 (80 mM) or by extracellular application of phaclofen and 2-hydroxysaclofen (10 and 4 mM, respectively). The present study demonstrates that, in an acute model of epileptogenesis, spontaneous interictal spikes are fostered by a primary burst of fast action potentials that ride on a regenerative high-threshold, possibly calcium-mediated spike, which activates a recurrent, glutamate-mediated potential responsible for the entrainment of adjacent and remote cortical regions. The bursting activity is controlled by a GABA(B) receptor-mediated inhibitory synaptic potential.