Transient seizure clusters and epileptiform activity following widespread bilateral hippocampal interneuron ablation.

Interneuron loss is a prominent feature of temporal lobe epilepsy in both animals and humans and is hypothesized to be critical for epileptogenesis. As loss occurs concurrently with numerous other potentially pro-epileptogenic changes, however, the impact of interneuron loss in isolation remains unclear. For the present study, we developed an intersectional genetic approach to induce bilateral diphtheria toxin-mediated deletion of Vgat-expressing interneurons from dorsal and ventral hippocampus. In a separate group of mice, the same population was targeted for transient neuronal silencing with DREADDs. Interneuron ablation produced dramatic seizure clusters and persistent epileptiform activity. Surprisingly, after one week seizure activity declined precipitously and persistent epileptiform activity disappeared. Occasional seizures (≈1/day) persisted to the end of the experiment at four weeks. In contrast to the dramatic impact of interneuron ablation, transient silencing produced large numbers of interictal spikes, a significant but modest increase in seizure occurrence and changes in EEG frequency band power. Taken together, findings suggest that the hippocampus regains relative homeostasis - with occasional breakthrough seizures - in the face of an extensive and abrupt loss of interneurons. Significance Statement Interneuron loss is hypothesized to play a critical role in epileptogenesis, however, the co-occurrence of interneuron loss with other potentially epileptogenic changes has made assigning causal relationships challenging. Here, we utilized an intersectional genetic approach to delete hippocampal interneurons. Treatment produced robust - but transient - seizure clusters in the animals followed by a relative recovery with infrequent seizures. Findings support a critical role for interneuron loss in epileptogenesis, but also imply the existence of mechanisms that can rapidly restore excitatory/inhibitory balance in the brain.