Evidence that repetitive seizures in the hippocampus cause a lasting reduction of GABAergic inhibition

Abstract

1. A method was developed to quantify paired-pulse depression of population spikes in the CA1 region of the hippocampus of urethane-anesthetized rats with paired stimuli to the contralateral CA3 region at various states of excitability of pyramidal cells. This method was applied to measure changes following recurrent seizures, a single seizure, or long-term potentiation (LTP). 2. In naive animals paired-pulse depression was highly variable at low stimulus intensities, but constant above a certain "threshold" stimulus intensity. The potency of paired-pulse depression also depended on the time between paired stimuli, being maximal at an interpulse interval of 20 ms. The general relationships of paired-pulse depression to stimulus intensity and to interpulse interval were unaltered after LTP, after a single seizure, and after recurrent seizures, but there were quantitative changes in the last two cases. 3. A variety of pharmacologic agents known to interact with GABAergic inhibition were studied for their effect on paired-pulse depression. These agents affected earlier phases of paired-pulse depression (interpulse intervals less than or equal to 100 ms). The GABA agonist muscimol and the benzodiazepine diazepam enhanced paired-pulse depression whereas the GABA antagonist bicuculline decreased it. 4. Repeated seizures elicited by trains (50-Hz, 10-s durations every 5 min) of electrical stimuli to the hippocampus were associated with progressive lengthening of afterdischarges. 5. Recurrent seizures caused a statistically significant reduction in the potency of earlier phases of paired-pulse depression. There was an increase in the potency of later phases of paired-pulse depression after recurrent seizures, but this was not statistically significant. These changes were present for at least 2 h after the last seizure. 6. An antidromic-orthdromic paired-pulse protocol was used to exclude slow conductance changes as the cause of paired-pulse depression. Paired-pulse depression measured with this method was also decreased by recurrent seizures. 7. A single seizure caused a small reduction in paired-pulse depression that dissipated in less than an hour. 8. A single seizure caused LTP of stimulus intensity versus population spike curves whereas recurrent seizures attenuated or even reversed the potentiation, leading to a rightward shift of the curves relative to control curves. When LTP was produced by a less intense stimulus train (50-Hz, 400-ms duration), there were no associated seizures nor was there any change in paired-pulse depression.(ABSTRACT TRUNCATED AT 400 WORDS)