In children, radiation exposure of the brain occurs during the treatment of intracranial malignancies, prophylactic therapy for leukemia and in whole body exposures for bone marrow transplantation. A major adverse effect of brain irradiation in these patients is cognitive dysfunction, involving learning and memory impairments, and younger children are particularly sensitive. The pathogenesis of such changes is not well understood, but it has been hypothesized that the hippocampus a major component of the medial temporal lobe memory system, is involved. Disturbances in hippocampal functioning reduce spatial learning and memory performance and the ability to explore the environment adequately, all of which are easily assessed in mice. The granule cells of the dentate gyrus of the hippocampus are involved in spatial memory, and radiation-induced cellular depletion of the granule cell layer has been implicated in cognitive deficits. We have recently shown that proliferating neural precursor cells of the hippocampus, which are responsible for producing granule cells, are particularly sensitive to x-rays. We hypothesize that radiation-induced loss of neural precursor cells in young animals will result in impairments in specific hippocampus-dependent cognitive functions, and that precursor cell loss and subsequent cognitive deficits can be ameliorated by agents that affect early radiation response. The overall objective of this proposal is to establish a mouse model to test this hypothesis. There are 4 specific aims in support of our objective: 1) Determine the dose response for radiation-induced apoptosis in the dentate subgranular proliferative zone (SGZ) of the mouse hippocampus as a function of animal age; 2) Determine if radiation-induced reduction of proliferating SGZ precursors in young animals is related to the severity of cognitive deficits after x- irradiation; 3) Determine the dose and administration schedule of the caspace inhibitor z-VAD-fmk required to inhibit radiation-induced apoptosis in proliferating SGZ precursor cells in young animals; and 4) Determine if inhibition of apoptosis in SGZ precursor cells ameliorates radiation-induced cognitive deficits in young animals.
