Regulation of estradiol synthesis in the hippocampus

The steroid hormone estradiol is not only produced in the reproductive tract but also in the brain. Aromatase, the enzyme that converts testosterone into estradiol, has been detected in various brain regions in many species, including human, mouse and rat. Our laboratory is focused on the role of aromatase and estradiol in the hippocampus, a brain region that is crucial for learning and memory. Previously, we demonstrated that hippocampus-derived estradiol is an important regulator of synapse formation and maintenance. Furthermore, the locally produced estradiol influences neurogenesis in the hippocampus.

However, the regulation of aromatase transcription and activity in the hippocampus is barely understood. Using molecular approaches we aim at identifying the underlying mechanisms of the regulation of aromatase transcription in the hippocampus. In a recent paper, we demonstrated that Gonadotropin Releasing Hormone (GnRH) regulates hippocampal estradiol synthesis in an in-vitro model. These findings suggest, that factors that are known to regulate the gonadal aromatase expression, like GnRH, are also involved in the aromatase regulation in the hippocampus. Another factor that might play a role in hippocampal aromatase transcription is SF-1. SF-1 is a transcription factor that is known to induce aromatase expression in the ovary and that is also expressed in the rat hippocampus. Using a brain-specific SF-1 knock out mouse we are going to elucidate its role in hippocampal aromatase expression.

The role of hippocampal aromatase in Alzheimer’s Disease

Recent studies using aromatase knock-out mice, showed that the lack of local production of estradiol results in an early development of symptoms of Alzheimer’s Disease (AD) in AD-model mice that express a mutant form of the amyloid precursor protein (APP). These findings imply that locally produced estradiol might be protective against this disease. Currently, very little is known on whether aromatase expression is altered in AD patients. The Alzheimer’s Disease Center at UT Southwestern provides human material that will allow us to answer this question. Furthermore, we use AD mouse models to investigate the time course of potential changes in aromatase expression in the progression of the disease and as an experimental approach.