Targeted Interneuron Ablation in the Mouse Hippocampus Can Cause Spontaneous Recurrent Seizures

Abstract

The death of GABAergic interneurons has long been hypothesized to contribute to acquired epilepsy. These experiments tested the hypothesis that focal interneuron lesions cause acute seizures (i.e., status epilepticus, SE) and/or chronic epilepsy (i.e., persistent spontaneous recurrent seizures, SRSs). To selectively ablate interneurons, Gad2-ires-Cre mice were injected unilaterally in the CA1 area of the dorsal hippocampus with an adeno-associated virus containing the diphtheria toxin receptor (DTR). Simultaneously, an electrode, connected to a miniature telemetry device, was positioned at the injection site for chronic recordings of local field potentials (LFPs). Two weeks after virus transfection, intraperitoneal injection of DT consistently caused focal, specific and extensive ablation of interneurons. Long-term, continuous monitoring revealed that all mice with DT-induced interneuron lesions had SRSs. Seizures lasted 10’s of seconds and inter-seizure intervals were several hours (or days); therefore, these interneuron lesions did not induce SE. The SRSs occurred 3-5 days after DT treatment, which is the estimated time required for DT-induced cell death; therefore, induction of SRSs occurred without the latent period typical of acquired epilepsy. In 5 of 6 DT-treated mice, SRSs stopped within days, suggesting that the DT-induced interneuron lesions did not usually cause epilepsy. In one mouse, however, SRSs occurred for ≥34 days after interneuron ablation, similar to epilepsy after experimental SE. Sham-control mice had no detectable seizures, confirming that the SRSs were due to ablation of interneurons. These data show that selective interneuron ablation consistently caused SRSs but not SE; and, at least under the conditions used here, interneuron lesions rarely led to persistent SRSs (i.e., epilepsy).

Significance Statement Cell death, including interneuron loss, is a common pathology of the brains of human patients and animal models of acquired epilepsy. However, the degree to which interneuron loss is a cause of or is a result of seizures remains unknown. By specifically ablating interneurons of the dorsal hippocampus, the degree to which selective interneuron lesions could cause spontaneous seizures was examined with long-term, continuous recordings of behavior (i.e., with video) and local field potentials (LFPs). Interneuron loss consistently caused seizures, which (1) were separated by intervals too long to be status epilepticus and (2) usually stopped after only a few days, and thus did not appear equivalent to epilepsy.