Abstracts

Rationale: Cognitive comorbidities, including memory deficits, have a significant impact on the patient with epilepsy's quality of life. Nevertheless, there are still no treatments currently available. Epilepsy patients exhibit varying degrees of cell death and hippocampal sclerosis (HS). However, not all patients who have memory impairments exhibit severe cell loss, and cell loss with HS is not always associated with memory deficits. These observations suggest that, at least in certain patients, more subtle changes in hippocampal physiology may underlie memory dysfunction. Animal models of epilepsy exhibiting memory dysfunction in the absence of cell loss may facilitate the discovery of treatments for these detrimental comorbidities. To identify such a model, we tested the hypothesis that corneal kindled mice exhibit dentate gyrus (DG) mediated memory and synaptic plasticity deficits in the absence of overt neuronal loss. Upon confirming these deficits, we explored the cellular and synaptic changes in the DG of corneal kindled mice that may mechanistically contribute to their cognitive dysfunction. Methods: C57Bl/6 mice were stimulated twice daily via corneal stimulation (1.5 mA/60 Hz/3 sec) and considered fully kindled after experiencing five consecutive stage five seizures. Three days later, stimulated and non-stimulated mice were tested in a DG-dependent spatial memory test (the metric task). Following behavioral testing, brains were processed for immunohistochemistry to evaluate neuronal density and astrogliosis or were used for in-vitro brain slice electrophysiology to test for changes in synaptic transmission along the perforant path (pp) using input-output (I/O) curves, paired-pulse ratios (PPR), long-term potentiation (LTP), and changes in excitatory or inhibitory synaptic transmission at DG granule cell (DGC) synapses. Results: Corneal kindled mice exhibited DG-dependent spatial memory deficits in the absence of overt neuronal loss in the hippocampus (including DGCs and the hilus). Additionally, brain slices from corneal kindled mice exhibited attenuated LTP at the pp-DGC synapse. DGCs from kindled mice had an increased post-synaptic response to pp stimulation and a reduced population spike threshold without any changes in PPR. Lastly, DGCs from kindled mice had increased membrane resistances and received spontaneous excitatory postsynaptic currents (sEPSCs) with increased amplitudes. No differences in inhibitory synaptic transmission were observed. Conclusions: Corneal kindled mice exhibit DG-mediated spatial memory and synaptic plasticity deficits in the absence of overt hippocampal damage, and DGCs in corneal kindled mice have altered membrane resistances and synaptic properties consistent with hyperexcitability. We posit that this hyperexcitability and attenuated synaptic plasticity contribute to DG-mediated spatial memory impairments in corneal kindled mice. Thus, these mice may represent a novel model for the development of therapies to treat epilepsy-related memory deficits. Funding: The Waterford School, Sandy, UT 84093-2902, U.S.A., and Juan Diego Catholic High School, Draper, UT, 84020-9035, U.S.A.