| Popis: |
The data from the present studies suggest that granule cells in different stages of neuronal differentiation may be differentially susceptible to changes in their cellular structure and survival following an epileptogenic stimulus. Recent work in the field has focused on the development of dendritic abnormalities with respect to immature neurons or newly generated neurons following exposure to an epileptogenic stimulus. In Chapter 2, we show for the first time that fully differentiated granule cells are capable of dendritic rearrangement. Specifically, we have shown that previously established apical dendrites shift to the basal portion of the cell as the somata of these cells radially migrate up an adjacent primary dendrite towards the dentate molecular layer. In doing so, dendritic branches on this dendrite become a new primary dendrite. We also propose that this migration underlies the dispersion of the granule cell layer, which was previously suggested by other laboratories; however, the utility of organotypic explant cultures made from Thy1-YFP mice allowed us for the first time to observe fully differentiated granule cell migration and their contribution to the dispersion of the granule cell layer. Granule cell dispersion and distortions to granule cell dendritic structure are common pathologies of the epileptic brain. Both phenomena also occur in adult animal models of epilepsy.Using bi-transgenic Gli-CreERT2+/-;Green fluorescent protein (GFP) reporter+/- mice, data from Chapter 3 suggests that the pool of hippocampal subventricular zone and/or subgranular cell layer neural progenitor cells active several days prior to a prolonged seizure become disrupted following early-life seizure activity. Specifically, fewer cells within the dentate gyrus were labeled with GFP, and associated with decreased numbers of progenitor cells, immature and mature granule cells. Additionally, we are the first laboratory to show that early-life seizures disrupt the integration of granule cells, which has been a ‘hot’ topic in studies using adult models of epilepsy. In Chapter 4, we used the same bi-transgenic mice, but in an adult model of epilepsy. From this study, we found that the pool of subgranular zone progenitor cells producing progeny following seizures become disrupted, and at later time points, give birth to fewer new granule cells. Additionally, this study implicates that granule cells born during the first week following a seizure may exhibit an accelerated rate of maturation. The results of these studies will hopefully spur further research into the underlying cellular signaling pathways involved in the formation of basal dendrites on dentate granule cells, etcopic localization of granule cells to the hilus and dentate molecular layers and granule cell layer dispersion. Additionally, future studies of cell-fate mapping in the early-life seizure and adult model of epilepsy should include the use of alternate tamoxifen injection time points to determine if progenitors active before or after an epileptogenic stimulus respond differently than the conditions tested here. |
