Abstracts

Rationale: Dysregulated hippocampal neurogenesis is a prominent feature of temporal lobe epilepsy (TLE). Anatomical data indicate that most dentate granule cells (DGCs) generated in response to an epileptic insult develop features that promote increased excitability, including ectopic location, persistent hilar basal dendrites (HBDs) and mossy fiber sprouting. However, some appear to integrate normally and promote reduced excitability. Much of what is known about aberrant DGC neurogenesis comes from anatomical data; relatively few studies have investigated the physiological properties of age-defined cells. Using a retroviral (RV) GFP reporter to birthdate DGCs, our laboratory found that DGCs that were mature at the time of status epilepticus (SE inciting epileptogenic injury in this model) are resistant to morphological abnormalities, while the majority of those born after SE display TLE-related pathology. This suggests that post-SE generated DGCs promote pathological function while established DGCs retain normal function. To examine the relationship between DGC age and synaptic inputs, we recorded from RV birth-dated DGCs born either neonatally or during adulthood in epileptic or intact animals.Methods: We stereotaxically injected RV-CAG-GFP into postnatal day (P) 7 or P60 rat DG to label neonatally- or adult-born DGCs, respectively. SE was induced with pilocarpine at P56. Recordings were made between 8-14 weeks after SE from age-defined cells in acute hippocampal slices using whole-cell voltage-clamp. Spontaneous excitatory post-synaptic currents (sEPSCs) were measured, and frequency and amplitude quantified. After recordings, cells were filled with biocytin and slices immunostained to examine cell morphology.Results: We found that, in TLE tissues, both adult-born and neonatally-born populations of DGCs showed receive increased sEPSC frequency and amplitude compared with age-matched controls. These changes occurred in the absence of changes in input resistance, membrane potential, and action potential threshold. Recordings of miniature EPSCs are ongoing.Conclusions: Our results suggest DGCs receive increased excitatory input in epileptic animals regardless of whether they were generated in the neonatal period or adult-born after SE. Concurrent experiments will assess inhibitory inputs within the same populations of cells. Ongoing analysis will also determine whether there is a correlation between degree of aberrant morphology and amount of excitatory input.