| Co-Investigator(Kenkyū-buntansha) |
TSUTSUI Kazuyoshi Hiroshima University, Faculty of Integrated Arts and Sciences, Professor, 総合科学部, 教授 (20163842)
KIMOTO Tetsuya The University of Tokyo, Graduate School of Arts and Sciences, Research Associate, 大学院・総合文化研究科, 助手 (60292843)
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| Research Abstract |
Neurosteroids, produced de novo in the brain, regulate learning and memory processes by acutely modulating the ion conductivity of neurotransmitter receptors in hippocampal neurons. The pathway of neurosteroidogenesis and the regulation mode of neuronal signal transmission have not been well-elucidated. In the present study, we have discovered that a neurosteroidogenic system, composed of cytochrome P450scc, hydroxysteroid sulfotransferase, steroidogenic acute regulatory protein (StAR), 3beta-hydroxysteroid dehydrogenase, P450c17 and P450arom, localizes in pyramidal neurons and granule neurons in the rat hippocampus. This indicates that the main source of neurosteroids in the hippocampus is not glial cells, as has been believed, but neurons. Furthermore, we have found, with HPLC analysis and radioimmunoassay, that cholesterol is actively metabolized to 17beta-estradiol (E2) through precursor steroids, pregnenolone, dehydroepiandrosterone (DHEA) and androsterone. We have also found that
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the rate of neurosteroidogenesis was regulated through mitochondrial StAR processing, which was acutely induced by Ca^<2+> influx via NMDA receptors. P450c17 enzyme and its activity (DHEA synthesis) were demonstrated for the first time in the mammalian brain, by which we can now regard downstream steroids, such as E2 and teststerone, as 'true' neurosteroids.
We also examined the acute effect of neurosteroids on the signal transmission of hippocampal neurons. Pregnenolone sulfate (500 nM) was observed to potentiate Ca^<2+> influx via NMDA receptors very acutely (within 1 sec), which resulted in the reduction in the strength of tetanus stimulation required to induce LTP (from 100 Hz, 1 sec to 30 Hz, 0.5 sec) in hippocampal slices prepared from 4-week-old male Wistar rats. Nitric oxide production in hippocampal neurons was also acutely promoted by the application with pregnenolone sulfate. A short time treatment with E2 (1-100 nM, 20 min) suppressed LTP formation, in dose-dependent manner, in hippocampal slices obtained from 4-week-old male Wistar rats and stimulated with tetanus stimulation (100 Hz, 1 sec). On the other hand, the same E2 treatment potentiated LTP in hippocampal slices prepared from 10-week-old male rats. These results suggest that the mode of E2 action on neuronal signal transmission varies depending on the age of animals from which hippocampal slices were obtained. Corticosterone, a most potent stress steroid, suppressed LTP induction and Ca^<2+> influx via NMDA receptors in hippocampal slices. This result might give the cell physiological basis for PTSD induced by the acute and strong stress. Less
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