Abstracts

Rationale: Temporal lobe epilepsy (TLE) is typified by hippocampal hyperexcitability arising in part from altered activity and connectivity of hilar neurons. In animal models of TLE and in human patients, network reorganization in the hilus leads to profound mossy cell death as well as mossy fiber sprouting and increased kainate receptor (KAR) expression in the dentate gyrus, which contribute to hippocampal hyperexcitability. The “dormant basket cell” and “irritable mossy cell” hypotheses state that mossy cell death disinhibits the dentate gyrus or that remaining mossy cells after seizure-induced cell death become hyperexcitable. Hence changes in mossy cell excitability and in hilar synaptic connectivity are thought to contribute to pathological hilar hyperexcitability.Methods: We are examining physiological changes that occur in the hilar circuit in the Scn2aQ54 mouse, which reproduces the network-level reorganization and cell death seen in TLE. We hypothesize that, in this model, mossy cells will be hyperexcitable and that kainate receptor function will be altered at hilar synapses. To address these hypotheses, we are making loose-seal and whole-cell patch clamp recordings of mossy cells and granule neurons in acute slices from Scn2aQ54 mice and wildtype (WT) littermates. Recordings are made after the onset of spontaneous seizures; seizure frequency is determined using video recordings. We will examine the intrinsic physiology of mossy cells and kainate receptor function at mossy fiber – mossy cell and mossy cell – granule cell synapses.Results: Our initial results demonstrate that mossy cell excitability is not increased in Scn2aQ54 mice: spontaneous and maximum firing rate were not different between Scn2aQ54 mice and WT littermates (spontaneous firing rate: 2.2 ± 0.9 Hz in Scn2aQ54 and 1.8 ± 0.5 Hz in WT; maximum firing rate: 71.29 ± 11.89 Hz in Scn2aQ54 and 44.43 ± 4.59 Hz in WT). In fact, mossy cell input resistance in Scn2aQ54 mice was lower than in WT littermates, a change often associated with a decrease in excitability (182.04 ± 23.20 MΩ in Scn2aQ54 and 300.64 ± 12.92 MΩ in WT; P<0.005). Hence our initial results suggest that mossy cells are not hyperexcitable in Scn2aQ54 mice, which is inconsistent with the irritable mossy cell hypothesis. In addition, mossy cell number was not noticeably decreased in Scn2aQ54 mice at this stage of disease progression. Ongoing experiments examine changes in synaptic strength and kainate receptor function at hilar synapses as well as correlate physiological changes with seizure frequency.Conclusions: This study of hilar physiology will shed light on the cellular and synaptic alterations which underlie hilar network hyperexcitability, providing a framework by which future studies can target these pathological changes to alleviate seizures associated with TLE. Funding from T32 AG20506 (NIA to TH), R21 NS090040 (NINDS to GTS), and R01 NS053792 (NINDS to JAK).