Abstracts

Rationale: Bath application of the K+ channel blocker 4-aminopyridine (4AP) can induce epileptiform synchronization in the in vitro brain slice preparation without interfering with GABAA receptor-mediated inhibition and, actually, even enhancing it. Here we tested the hypothesis that similar electrographic epileptiform patterns occur in vivo following systemic 4AP injection. Methods: Sprague-Dawley rats (n = 13) were implanted with bipolar electrodes aimed at the hippocampal CA3 region, entorhinal cortex, subiculum, dentate gyrus and amygdala. Animals were then injected with a single dose of 4AP (4-5 mg/kg, i.p.) and EEG recordings and video-monitoring were obtained. Results: 4AP induced convulsive or non-convulsive seizures in 12 out of 13 rats along with generalised fascicular twitching, wet-dog shakes and myoclonic jerks. On the EEG, we observed in 7/12 animals (58.3 %) long-lasting interictal spikes from the subiculum before the occurrence of the first seizure. Once seizures had started, interictal spikes occurred in all regions and had no fixed site of origin. Seizures induced by 4AP often initiated in the entorhinal cortex and CA3 and were often convulsive (48/59, 81.3%). Finally, 4AP also induced highly rhythmic theta (6-11 Hz) oscillations in CA3 and entorhinal cortex, before seizure occurrence. Conclusions: Our findings indicate that 4AP administration in vivo leads to a specific type of interictal activity, behavioral symptoms and network oscillations known to be linked to enhanced GABAergic inhibition. We propose that 4AP-induced ictogenesis reflects the interaction between excitatory and inhibitory processes.