- Focal injection of a minute quantity of tetanus toxin into the rat neocortex induces chronic epileptogenesis. Within a day, spontaneous and stimulus-evoked paroxysmal discharges appear in widespread regions of both hemispheres and this lasts for at least nine months. Tetanus toxin blocks transmitter release, apparently by catalysing the breakdown of synaptobrevin, a synaptic protein. It specifically binds to neuronal membranes but its potent epileptogenic properties have been ascribed to a higher affinity for inhibitory neurons. Following focal injection of tetanus toxin into the hippocampus a long-lasting epileptic syndrome also develops. During the early part of the syndrome GABA release is depressed in slices from the injected side, but not in slices from the contralateral, secondary focus. In the present experiments on neocortex, release of radiolabelled GABA was measured from primary and secondary epileptic foci induced by unilateral focal injection of tetanus toxin into the parietal cortex. By four weeks after the injection, no differences were detected in GABA release from any neocortical site in control or toxin-injected animals, despite the persistence of profound epileptic activity in slices from the latter. At earlier times (1.5 days) after the toxin injection, however, release was significantly depressed in both hemispheres. The results indicate that at first, the toxin induces focal neocortical epileptogenesis by directly impeding GABAergic synaptic transmission but that with time there is a recovery from this initial effect. We propose, as has also been suggested for other models, that the initial epileptogenesis leaves in its wake a long-lasting change in the local functional connectivity, such that the neocortex is rendered permanently epileptic.