Development and Characterization of Inducible Astrocyte-Specific Aromatase Knockout Mice

Simple Summary Recent work has shown that the steroid hormone17 beta-estradiol (E-2) is also produced in the brain in both neurons and astrocytes. The current animal models for depleting E-2, specifically in astrocytes, are non-inducible, which can provide a developmental confound. It would be advantageous to have an inducible knockout model where the E-2 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 E-2 specifically in the astrocytes of adult mice. The characterization of the inducible knockout mice confirmed that aromatase and E-2 were depleted specifically in the astrocytes of the adult mice. The study further revealed that astrocyte-derived E-2 had a significant role in protecting the brain from cerebral ischemia (stroke) and regulated both the astrocyte and microglia activation after a cerebral ischemia. 17 beta-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 E-2 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 E-2 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 E-2 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 E-2 (ADE(2)) 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 ADE(2) in the brain.

Automated summary

Recent research has found that the steroid hormone 17 beta-estradiol (E-2) is produced in the brain by both neurons and astrocytes. A new inducible knockout mouse model was created to specifically deplete the E-2 in astrocytes of adult mice, providing a better research model for studying brain-derived E-2 and its functions. The characterization of this mouse model confirmed the specific depletion of aromatase and E-2 in astrocytes, and revealed the neuroprotective role of astrocyte-derived E-2 in cerebral ischemia.