Abstracts

Rationale: During the development of epilepsy in adult animals, newly-generated granule cells integrate abnormally into the hippocampus. These new cells migrate to ectopic locations in the hilus, develop aberrant basal dendrites and contribute to mossy fiber sprouting, whereas mature granule cells do not appear to contribute to these pathological changes. Newborn granule cells also exhibit changes in apical dendrite structure and dendritic spine number, however, whether mature cells are similarly resistant to the development of these latter pathologies is not clear. Methods: To address this question, Thy1-GFP mice, in which a subset of dentate granule cells expresses GFP, were treated with BrdU either one-two weeks or two months before pilocarpine-induced status epilepticus. Animals were sacrificed one month after status epilepticus, and the apical dendritic structure of BrdU-birthdated, GFP-expressing granule cells was examined. Granule cells that were mature at the time of status (born two months before the insult) and cells that were immature at the time of status (born one-two weeks before the insult) were compared to their respective age-matched granule cells from control (non-epileptic) animals. Results: Immature granule cells exposed to status epilepticus frequently exhibited basal dendrites and distorted apical dendritic trees when examined one month later. By contrast, mature cells exposed to status lacked basal dendrites and exhibited normal apical dendrites one month after status. Both immature and mature granule cells exposed to status, however, exhibited reductions in spine density and spine number relative to age-matched cells from control animals. Conclusions: Together, these data demonstrate that while mature granule cells are resistant to developing the gross structural abnormalities exhibited by younger granule cells, they show similar plastic rearrangements of their dendritic spines. The reductions in spine density evident among these cells imply fewer synaptic inputs, perhaps reflecting homeostatic changes. Physiological studies, however, will be required to test these predictions. Importantly however, the present findings demonstrate that granule cells exhibit a range of plastic changes in the epileptic brain, and the nature of these changes depends on cell age. Understanding the interplay of changes among different age-subpopulations of granule cells is likely to be important for understanding dentate function in the epileptic brain.