Abstracts

Rationale: A selective loss of part of the overall population of GABAergic interneurons is a seminal component of many forms of human epilepsy, and is manifest in many animal models of acquired epilepsy, including those based on chemoconvulsant-induced status epilepticus. The current study specifically examines how selective interneuron loss in the dorsal CA1 area of the hippocampus induces epileptiform activity, and then whether interictal-like spikes and seizures progressively worsen during the subsequent weeks and months.Methods: Selective focal interneuron lesions were made by intrahippocampal injection of SSP-Saporin (isotonic saline in controls) into dorsal CA1 in the hippocampus of GAD67-GFP transgenic mice. Chronic recording electrodes were also implanted in the lesion area, and local field potentials (LFPs) were monitored continuously, along with video recordings of the subjects for a period of several weeks. LFP recordings were analyzed for the occurrance of inter-ictal-like paroxysmal events (hippocampal sharp waves generally lasting 50-100 msec), and frank seizures. Results: Preliminary data revealed spontaneous interictal-like spiking activity in 10 animals. There was no initial indication of seizure-like activity arising from these highly-localized interneuron-specific lesions in these animals. After a period of several weeks, however, interictal-like spiking activity developed into full-blown seizures in 1 animal. Control animals did not develop seizures. Single, isolated sharp wave bursts consistent with normal hippocampal activity were observed in the LFP records of these animals, but they were distinct from SSP-Saporin-injected animals in that these bursts were not repetitive. Histology confirmed that SSP-Saporin was effective in removing the majority of substance P receptor-expressing cells within a small, well-defined lesion site, leaving principal cells intact.Conclusions: The current data suggest that disruption of the local GABAergic interneuron population may be a key event that triggers alteration of neural networks in the hippocampus, leading to paroxysmal events and ultimately seizures. Although interneuron lesions alone were seen to generate inter-ictal-like activity within several days following surgery, full-blown seizure activity was not observed until several weeks later. This delay in onset is suggestive of other factors besides interneuron loss at play in the generation of seizures and the development of epilepsy. Thus, loss of local inhibition may be a necessary, but not sufficient condition for epileptogenesis.