HIPPOCAMPAL PLASTICITY FOLLOWING EPILEPTIFORM BURSTING PRODUCED BY GABA(A) ANTAGONISTS

The effects of epileptiform bursts on hippocampal excitability were examined in the CA3 region of guinea-pig hippocampal slices. Partial blockade of gamma aminobutyric acid(A) (GABA(A))-mediated inhibition by 500 IU/ml penicillin produced low frequency (2-4 Hz) ''pro-convulsant'' field potential oscillations. Normal spontaneous activity recovered less than 30 min after the penicillin was rinsed out providing bursting was prevented. Synchronized bursting rarely began on its own even after Ih in penicillin 500 IU/ml, but could be initiated in most slices after one to eight all-or-none bursts were evoked by low-intensity, low-frequency (0.2-0.25 Hz) stimuli. Spontaneous bursting, once initiated, persisted for at least 1h without further stimulation suggesting that a small number of bursts produced a long-lasting increase in excitability. Bursts disappeared more slowly than anticipated after convulsants were rinsed out and were followed by ''post-burst'' oscillations with different frequency characteristics than proconvulsant oscillations which persisted for at least 4h. Selective augmentation of evoked N-methyl-D-aspartate excitatory postsynaptic potentials appeared to be the critical first step in the initiation of bursting. The specific N-methyl-D-aspartate antagonist, 2-amino-5-phosphonovaleric acid (50-100 mu M), only partially suppressed pro-convulsant oscillations in partially disinhibited slices but completely prevented stimulus-triggered spontaneous bursting and prolonged hyperexcitability. Although N-methyl-D-aspartate receptors were necessary for the induction of bursting in partially disinhibited slices, they were not required to initiate bursting after more complete disinhibition. However, when 2-amino-5-phosphonovaleric acid was applied prior to and during perfusion with 2000 IU/ml penicillin, spontaneous bursts occurred at long, irregular intervals and lacked afterdischarges. These bursts rapidly disappeared upon penicillin washout and were not followed by persistent post-burst oscillations. N-methyl-D-aspartate antagonists applied only after bursts already established in penicillin blocked the afterdischarges but did not reduce the burst frequency. These observations indicate that epileptiform bursts can produce long-lasting, hippocampal hyperexcitability. The induction of these plastic changes requires N-methyl-D-aspartate receptor activation which then enhances both N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor mechanisms. Furthermore, N-methyl-D-aspartate excitatory postsynaptic potentials can participate in triggering spontaneous bursts but this role is masked once plasticity has occurred. Partial disinhibition produces a pro-convulsant state which does not induce long-lasting changes in hippocampal excitability but renders the neuronal network vulnerable to develop persistent epileptiform bursting with small additional excitatory inputs. These bursts then induce long-lasting, N-methyl-D-aspartate-dependent changes in neuronal function which not only increase the probability of bursting but also produce network oscillations which persist long after removal of the convulsant. These post-burst oscillations reflect a previously undescribed prolonged hyper-excitability state of the hippocampus which is a direct consequence of seizure-like activity in vitro. Their similarity to electroencephalograph rhythms observed following seizures in patients with epilepsy suggest that this model of seizure-induced plasticity could be used to investigate the mechanisms by which seizures increase the susceptibility to further seizures and render anticonvulsants ineffective.