Silencing of Hippocampal Somatostatin Interneurons Induces Recurrent Spontaneous Limbic Seizures in Mice

Abstract

The hippocampus proper and the subiculum contain two major populations of somatostatin (SST)-containing interneurons, oriens-lacunosum moleculare (O-LM) cells projecting from the stratum oriens to the stratum lacunosum moleculare and bistratified cells with their cell bodies close to the pyramidal cell layer and axons terminating in the strata radiatum and oriens. Both types of interneurons innervate pyramidal cell dendrites and exert prominent feedback inhibition. We now investigated whether impairing this type of feed-back inhibition by selectively inhibiting GABA release from SST expressing interneurons in hippocampal sector CA1 and subiculum may be sufficient to induce spontaneous recurrent seizures. We injected transgenic mice expressing Cre-recombinase on the SST promoter unilaterally into the ventral CA1 sector and subiculum with an adeno-associated viral (AAV) vector expressing tetanus toxin light chain (TeLC) with its reading frame inverted in a flip-excision (FLEX) cassette. This treatment resulted in specific expression of TeLC and silencing of SST-containing interneurons. We continuously monitored the EEG and behavior of the mice for six weeks. Nine out of eleven mice within 10 days developed series of pre- or interictal spikes (IS, 21.4 ± 6.83 per week) and four mice exposed recurrent spontaneous seizures (SRS, 1.5 ± 0.29 per week). All 23 SRS observed were preceded by IS series. Our data demonstrate a critical role of feed-forward inhibition mediated by SST-containing interneurons suggesting that their sustained malfunctioning can be causatively involved in the development of TLE.