Decreased heterosynaptic and homosynaptic paired pulse inhibition in the rat hippocampus as a chronic sequela to limbic status epilepticus

Abstract

We studied a rat model of chronic epilepsy that shares key features with certain patients with temporal lobe epilepsy. This model relies on a previous period of limbic system status epilepticus established by focal stimulation to one hippocampus. Animals were examined 1 month after recovery from such status epilepticus and compared to unstimulated controls and to animals that received stimulation but did not develop status epilepticus. Two experimental procedures were employed to study changes in paired pulse inhibition of population spike (PS) discharges elicited in CA1 pyramidal cells. One procedure (homosynaptic) delivered two identical stimuli to the CA3 region contralateral to the recording site; the other procedure (heterosynaptic) delivered a conditioning stimulus to the ipsilateral angular bundle and a separate test stimulus to the contralateral CA3. For both procedures, influences of stimulus intensities and of interpulse intervals on the potency of paired pulse inhibition were determined. Based on the results, standardized protocols that assayed the maximal amount of paired pulse inhibition were developed. With the homosynaptic protocol, there was one period of inhibition (interpulse intervals up to 300 ms). Animals that previously experienced limbic status epilepticus had markedly less paired pulse inhibition under these conditions than did controls. The stimulated, non-status epilepticus animals were not different from controls. For the heterosynaptic protocol, there were 2 phases of paired pulse inhibition, early (< 50 ms) and late (> 300 ms), separated by a period of paired pulse facilitation. After status epilepticus there were, compared to controls, decreases in both early and late phases of inhibition. The stimulated, non-status epilepticus animals were not different from controls. For the paired pulse facilitation, there was no difference between the animals that experienced status epilepticus and controls. These findings indicate a profound and enduring disturbance of GABA-mediated inhibition in this model. The heterosynaptic paired pulse protocol deals with a number of confounding issues associated with the homosynaptic protocol in this regard. Furthermore, the results suggest the inhibitory disturbance is diffuse, affecting various inhibitory circuits in the hippocampus.