Abstracts

Rationale: Our goal is to develop novel therapies for temporal lobe epilepsy (TLE). Due to a lack of suitable animal models, there has been little progress in developing therapies for TLE. While testing the hypothesis that “inhibiting inhibitory neurons” was sufficient to induce seizures, we discovered that a mild electrical kindling protocol of VGAT-Cre mice leads to spontaneous seizures. Methods: Mice were bilaterally injected into the hippocampus and subiculum and implanted with an EEG headset plus stimulating electrode. Mice were then electrically kindled (2x/day, @ 1.5x after-discharge threshold, ADT). Video/EEG was recorded 24/7. SRS began ~11 days after kindling. At the end of the experiment, mice were perfused, brains sliced, stained with validated antibodies, and then imaged. Results: In contrast to current models of TLE, seizures in VGAT-Cre mice occur in the absence of overt neuronal death, dentate granule cell dysgenesis, or aberrant mossy fibers. These mice express Cre recombinase under the control of the vesicular GABA transporter (VGAT), a gene that is specifically expressed in GABAergic inhibitory neurons. The insertion of Cre disrupts the expression of VGAT mRNA, protein, and impairs GABA release in the hippocampus. Conclusions: Considerable evidence supports the GABA hypothesis of epilepsy, which for TLE can be restated as: dysfunction of hippocampal GABAergic neurons leads to recurrent activation and the formation of seizure focus. Spontaneous seizures in kindled VGAT-Cre mice have an ideal frequency of 1-2 seizures/day for screening novel therapeutics. Funding: No funding