Suppression of 4-aminopyridine-induced epileptogenesis by the GABAA agonist muscimol

Bath application of muscimol to hippocampal slices taken from immature rats suppressed both spontaneous and electrically evoked epileptiform activity produced by 4-aminopyridine (4-AP). Epileptiform events consisted of ictal-like discharges that were up to 30 sec in duration and interictal burst-like discharges. The latter were often followed by brief synchronized afterdischarges that were less than 1 sec in duration. During the transition period to suppression, individual pyramidal cells did not hyperpolarize in response to muscimol, but instead underwent a gradual depolarization that averaged 8.5 mV. At the same time, the input conductance of these cells increased 2-3-fold. Concurrently the ictal-like discharges transiently increased in duration and then abruptly ceased. In most instances the ictal-like events were replaced by large slow depolarizing events. Orthodromic stimulation recruited these slow depolarizations in a graded manner. However, at high stimulus intensities and at unusually long latencies ictal-like discharges were evoked. This suggests that muscimol raises the threshold for the generation of ictal-like discharges but leaves the underlying physiological processes intact. The combined use of 4-AP and muscimol in immature hippocampal slices may prove to be useful for the study of the various physiologic processes that contribute to the genesis of seizures in immature hippocampus. In addition, results of these studies are relevant in light of the proposed use of GABA agonists in anticonvulsant therapy.