P2-064: Long-term cognitive and behavioral response, and liquid crystalline states of brain mitochondrial membrane in estrogen-treated mice exposed to low-dose radiation in utero

Abstract

Estrogen has been recently shown to play a neuroprotective role apart from popular view of its functions in human reproduction. In our research, we focused on the long–term membrane effects of estrogen on brain mitochondria and correlated these findings with its beneficial effects on cognitive and behavioral skills. Using an in utero radiation model of mice, the liquid crystalline (LC) organization of mitochondrial membrane from 60–day old mice was investigated by analyzing the self–organized LC textures, thermotropic transitions, and measured its lateral mobility. Various behavioral and cognitive tests were done. The organization of brain mitochondrial membranes of adult mice irradiated in utero at 17 dpc exhibited a decrease in unit texture size from 11.2–16.68 μm in control mouse to 5.58–11.12 μm in 1.0 and 1.5 Gy–irradiated mice. The ability of lyotropic LC domains to undergo intermediary phase changes and aggregate into more complex structures, e.g. coarse mosaic and pseudoisotropic textures, was ablated in the fetally–irradiated mice and this was not reversed even with post–natal treatment of 25 μg estradiol s.c. on day 5. Interestingly, estradiol treatment increased mitochondrial membrane fluidity in irradiated mice based on the calculated lateral diffusion coefficients from the quantum ratio, I' (excimer intensity)/I (monomer intensity) with 1–pyrene dodecanoic acid as probe. The effects of estradiol on lateral diffusion are not dependent on the radiation dose used and the sex. The biophysical data is consistent with the cognitive skills and behavioral patterns of the mice. Our results provide new insights on the molecular mechanisms of how estrogen acts in dampening neurodegeneration from a concurrent biophysical and behavioral perspective.