title: Hippocampal plasticity following epileptiform bursting produced by GABAA antagonists.
abstract: The effects of epileptiform bursts on hippocampal excitability were examined in the CA3 region of guinea-pig hippocampal slices. Partial blockade of gamma-aminobutyric acidA (GABAA)-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 1 h 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 1 h 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 4 h. 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 microM), 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.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Wellesley Hospital, Toronto, Ontario, Canada.
authors.forename: J H
authors.initials: JH
authors.lastname: Schneiderman
authors.forename: C A
authors.initials: CA
authors.lastname: Sterling
authors.forename: R
authors.initials: R
authors.lastname: Luo
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology*; D000818:Animals; D004558:Electric Stimulation; D004827:Epilepsy / Q000503:physiopathology; D005071:Evoked Potentials / Q000187:drug effects; D018756:GABA Antagonists; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects*; D010406:Penicillins / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D012640:Seizures / Q000503:physiopathology; D013997:Time Factors
chemical_list: D018756:GABA Antagonists; D010406:Penicillins; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate