Abstracts

Neurogenesis persists in the adult human hippocampal dentate gyrus, but its role in temporal lobe epilepsy (TLE) is unknown. In experimental TLE, seizures initially stimulate neurogenesis, but neurogenesis declines in chronic epilepsy (Hattiangady et al, Neurobiol Dis 2004). Because adult dentate gyrus neurogenesis is implicated in learning and memory, its loss may contribute to cognitive deficits associated with TLE. To gain insight into the relationship of persistent neurogenesis and severity of human TLE, we examined markers of neural progenitors and cell proliferation in hippocampi surgically resected to treat TLE., Informed consent was obtained to study tissue from patients undergoing anterior temporal lobectomy or selective amydalo-hippocampectomy for medically refractory TLE. Resected tissue was immediately immersion fixed in 4% PFA, cryoprotected, frozen and cryostat-sectioned at 40 [mu]m thickness. Immunoperoxidase and immunofluorescence histochemistry was performed using antibodies to markers of cell proliferation (Mcm2, Ki67), neural progenitors (nestin, Sox3), and immature (class III [beta]-tubulin) and mature (NeuN) neurons. Double-label immunofluorescence also was done using some combinations of antibodies., Over 13 specimens have been collected to date, and they show varying degrees of mesial temporal sclerosis (MTS) pathology. Nestin-immunoreactive radial glia-like, putative stem cells were seen in the outer granule cell layer (GCL) in most specimens. Ki67+ and Mcm2+ cells appeared in the GCL and hilus, and putative immature neurons expressed [beta]-tubulin in the same regions. Infrequently, chains of Sox3-immunoreactive cells extended between the GCL and hilus, resembling migrating neuroblasts. Sox3+ cells appeared to co-express [beta]-tubulin but not Mcm2, nestin, or GFAP. Some of the double-labeled cells displayed an immature neuronal morphology. The pattern of Sox3 expression differed between severe and mild MTS: in mild cases, many Sox3+ cells appeared in the hilus and subgranular zone, and very few were seen in the GCL; with severe MTS, few Sox3-labeled cells were found in the hilus, and most of the dispersed GCL showed varying degrees of Sox3 immunoreactivity., Neural progenitors appear preserved in the hilus of TLE patients with mild MTS. In contrast, severe MTS is associated with diminished hippocampal progenitors and dentate granule cells appear to mis-express progenitor markers. These findings suggest that altered progenitor function and dentate granule cell differentiation contribute to epilepsy or memory dysfunction in human TLE., (Supported by University of Michigan Medical School)