EPILEPTIC ACTIVITY OUTLASTS DISINHIBITION AFTER INTRAHIPPOCAMPAL TETANUS TOXIN IN THE RAT

1. A single dose of tetanus toxin, injected under anaesthesia into one dorsal hippocampus of the rat, produces chronic epileptic foci involving both hippocampi. Generalized seizures occurred 1-6 weeks after injection and epileptic discharges were found in hippocampal slices in vitro. Here we measured the time course of decay of epileptic activity and the level of GABA(A) receptor-mediated inhibition in hippocampal slices 1-16 weeks after toxin injection in vivo. 2. Epileptic activity peaked in the dentate granule cell and CA3 pyramidal cell layers 2 weeks after toxin injection and at 4 weeks in CA1. Thresholds for evoking epileptic activity were lowest in the suprapyramidal blade of the dentate gyrus and area CA3c. Recovery from epileptic activity occurred more rapidly in the contralateral hippocampus. Polyspike activity ceased by 8 weeks and interictal activity by 16 weeks. Epileptic discharges could still be evoked from CA1 16 weeks after toxin injection. 3. The maximal monosynaptic fast inhibitory postsynaptic current (IPSC) conductance changes (g(IPSC)) decreased to <10% of control values at the time of peak epileptic activity and remained lower than controls for 4 weeks ipsilaterally. In the contralateral hippocampus, g(IPSC) fell to ca 50% of control values for the first 2 weeks. Responses to exogenous GABA remained unchanged. 4. After 8 weeks dentate granule cells had g(IPSC) Significantly larger than controls. No increase in g(IPSC) occurred in CA3. Epileptic activity persisted 8-10 weeks after recovery from disinhibition ipsilaterally and 4 weeks contralaterally. 5. Epileptic activity was seen when monosynaptic GABA(A) receptor-mediated IPSCs were normal or supranormal. At these times polysynaptic inhibition was still profoundly reduced. These observations provide strong evidence for long-term changes in the pattern of synaptic excitation contributing to a chronic epileptic syndrome following disinhibitory insult, and are consistent with weakened excitation of inhibitory neurones.