Sunday July 2, 2006 9:30-11:30 Hall 3D Discussion Group Session Plastic modifications during the transition between a normal brain and an epileptic one

Abstract

Abstract 1 J. Fritschy ( 1 University of Zurich, Institute of Pharmacology and Toxicology, Switzerland ) Adult hippocampal neurogenesis is enhanced in response to acute seizures. However, the significance of neurogenesis in temporal lobe epilepsy (TLE) remains disputed. Unilateral intrahippocampal injection of kainate (KA) in adult mice models morphological features (e.g., neuronal loss, granule cell dispersion) and occurrence of chronic recurrent seizures observed in human TLE. In this model, KA injection transiently increased cell proliferation bilaterally in the subgranular zone (SGZ). As a result, neurogenesis was stimulated in the contralateral dentate gyrus. In contrast, the epileptic hippocampus exhibited strongly reduced neurogenic potential, even after onset of recurrent seizures. Therefore, neurogenesis does not contribute towards the formation of the epileptic focus and may be affected when granule cell dispersion occurs. To investigate further the relationship between epileptogenesis and neurogenesis, we compared the differentiation of cells born shortly before and after KA injection. Immunohistochemical staining for doublecortin and PSA-NCAM, two markers of young neurons, revealed rapid down-regulation of both markers ipsilaterally, whereas they were increased transiently on the contralateral side. To determine whether KA treatment directly affects SGZ neural progenitors, dividing cells were prelabeled with 5′-bromo-2′deoxyuridine (BrdU) treatment before unilateral injection of KA. Double staining with the proliferation marker PCNA showed that prelabeled BrdU cells survived KA exposure and proliferated bilaterally. Unexpectedly, the neuronal differentiation of these cells, as assessed after two weeks with doublecortin and NeuN triple staining, occurred to the same extent as in control. Therefore, SGZ progenitor cells that were committed to a neuronal phenotype before KA treatment completed their differentiation despite the rapid down-regulation of doublecortin and PSA-NCAM. These findings suggest impaired fate commitment of proliferating cells in the lesioned dentate gyrus. Loss of neurogenesis in this TLE model likely reflects an irreversible alteration of the SGZ germinal niche during development of the epileptic focus and may therefore be relevant for human TLE.