Neurosteroids: Synthesis and Regulation

Georgetown University, Washington DC

Investigators

Abstract

Steroid hormones can have rapid effects on nerve cells in the brain, and are known to interact with binding sites in the brain. While peripheral endocrine organs supply many steroids, it is now known that brain tissue itself can synthesize some steroids. Glial cells can convert cholesterol to other compounds, including the steroid dehydro-epiandrostenone (DHEA), one of the main neuroactive steroids synthesized in the brain. In peripheral tissues a protein enzyme known as P450c17 is responsible for DHEA formation, but this enzymatic activity has not been found in the brain. This paradox led to controversy over the role of this enzyme in brain DHEA formation, and whether regulation of neurosteroid biosynthesis occurs via a brain-specific steroid biosynthetic pathway. To help settle this debate, this project develops a genetic model of a mouse with the P450c17 gene knocked out. The expression and activity of steroidogenic enzymes in the brain cells of these mice are examined to investigate the expression of a possible novel alternative pathway for DHEA synthesis. Results will be important to resolving a current controversy in neuroendocrinology. The impact will extend beyond neuroendocrinology by leading to a better understanding of the neurochemical pathways underlying brain function in general, and so will be important for neurochemistry, developmental neuroscience, and the biopsychology of stress and aging. The project also supports postdoctoral training.