Development and Characterization of Inducible Astrocyte-Specific Aromatase Knockout Mice.

Simple Summary: Recent work has shown that the steroid hormone17β-estradiol (E2) is also produced in the brain in both neurons and astrocytes. The current animal models for depleting E2, specifically in astrocytes, are non-inducible, which can provide a developmental confound. It would be advantageous to have an inducible knockout model where the E2 depletion in astrocytes could be performed in adult animals, so as to avoid this confound. Thus, in the current study, we created an inducible knockout mouse model to deplete the E2 specifically in the astrocytes of adult mice. The characterization of the inducible knockout mice confirmed that aromatase and E2 were depleted specifically in the astrocytes of the adult mice. The study further revealed that astrocyte-derived E2 had a significant role in protecting the brain from cerebral ischemia (stroke) and regulated both the astrocyte and microglia activation after a cerebral ischemia. 17β-estradiol (E2) is produced in the brain as a neurosteroid, in addition to being an endocrine signal in the periphery. The current animal models for studying brain-derived E2 include global and conditional non-inducible knockout mouse models. The aim of this study was to develop a tamoxifen (TMX)-inducible astrocyte-specific aromatase knockout mouse line (GFAP-ARO-iKO mice) to specifically deplete the E2 synthesis enzymes and aromatase in astrocytes after their development in adult mice. The characterization of the GFAP-ARO-iKO mice revealed a specific and robust depletion in the aromatase expressions of their astrocytes and a significant decrease in their hippocampal E2 levels after a GCI. The GFAP-ARO-iKO animals were alive and fertile and had a normal general brain anatomy, with a normal astrocyte shape, intensity, and distribution. In the hippocampus, after a GCI, the GFAP-ARO-iKO animals showed a major deficiency in their reactive astrogliosis, a dramatically increased neuronal loss, and increased microglial activation. These findings indicate that astrocyte-derived E2 (ADE2) regulates the ischemic induction of reactive astrogliosis and microglial activation and is neuroprotective in the ischemic brain. The GFAP-ARO-iKO mouse models thus provide an important new model to help elucidate the roles and functions of ADE2 in the brain. [ABSTRACT FROM AUTHOR]