Abstracts

Rationale: Cognitive and psychiatric dysfunction significantly impacts the quality of life of patients with epilepsy. Furthermore, these debilitating comorbidities may arise from the underlying neurobiology of epilepsy (primary), as a consequence of seizures (secondary), and/or as a side-effect of antiseizure drugs (iatrogenic). In all of these cases, pathophysiology is poorly understood and no effective treatments exist. Accordingly, rodent models of epilepsy with cognitive and/or psychiatric comorbidities are needed. Our previous work has demonstrated that electrically-induced acute seizure models have impaired dentate gyrus (DG) mediated spatial learning and memory and attenuated DG synaptic plasticity (Remigio et al. Neurobiol Dis. 2017; 105:221-234). However, an understanding of cognitive dysfunction in models that experience genuine spontaneous recurrent seizures (SRSs) is needed. Therefore, the aim of these experiments was to evaluate the effects of SRSs on DG-mediated cognitive function and synaptic plasticity in the intra-amygdala kainate (IAK) mouse model of temporal lobe epilepsy. Methods: Male C57Bl/6J mice were surgically implanted with cortical EEG electrodes and a guide cannula for microinjection of kainate (0.3 mg / 0.2 µL) into the basolateral amygdala to induce status epilepticus. Mice were monitored 24 hours per day, 7 days per week, via combined video-EEG to assess frequency of spontaneous seizures for 3 weeks. Coronal brain slices containing the hippocampus were prepared and field excitatory post-synaptic potentials (fEPSPs) were recorded in the DG to assess theta burst stimulation (TBS) induced long-term potentiation (LTP). IAK mice were also tested for spatial learning and memory dysfunction in a task reliant on the DG: the metric task. Mice were allowed to explore an arena that contained two dissimilar objects placed 30 cm apart for 15 min. After a 5-minute delay in a holding cage, the mice were allowed to explore a duplicate pair of objects now placed 8 cm apart. Performance was quantified as a Recognition Index (RID): (Novel – Familiar) / (Novel + Familiar). Results: IAK mice (N=9) experienced an average of ~1-2 SRSs per day. When tested in a task reliant on spatial pattern processing in the dentate gyrus (the metric task), IAK mice had significant impairments in performance compared to control mice (N=10) (Control RID: 0.36±0.06; IAK RID: 0.10±0.09; p=0.0281). In an open field paradigm, the IAK mice also showed significantly increased movement (control: 5.7±0.2 cm/s; IAK: 9.0±1.0 cm/s; p=0.0040) and decreased time in the center of the arena (control: 42±3%; IAK: 25±4%; p=0.0038). Finally, in a measure of experience-dependent synaptic plasticity, LTP at the perforant path – DG synapse in the IAK group was significantly attenuated (Control N=20 slices / 4 mice: 125.2±7.3%; IAK N=17 slices / 3 mice: 104.7±4.3%; p=0.0094). Conclusions: These results strongly suggest that IAK treatment significantly impacts cognitive function both in vivo and in vitro at the level of the dentate gyrus. Therefore, IAK mice may be useful as a tool to evaluate novel treatments for cognitive dysfunction associated with SRSs in patients with epilepsy. In addition, the IAK model is currently being evaluated for inclusion for antiseizure testing in the NINDS Epilepsy Therapy Screening Program.  Funding: HHSN271201600048C. (K.S. Wilcox, PI) NINDS, NIH, and support from the Waterford School and Juan Diego Catholic High School