Development and Characterization of Inducible Astrocyte-Specific Aromatase Knockout Mice

Area of Science:

• Neuroscience
• Endocrinology
• Molecular Biology

Background:

• 17β-estradiol (E2) functions as both an endocrine hormone and a brain neurosteroid.
• Existing mouse models for studying brain E2 have limitations.
• Astrocyte-derived E2 (ADE2) plays a significant role in brain function.

Purpose of the Study:

• To develop a tamoxifen (TMX)-inducible astrocyte-specific aromatase knockout mouse line (GFAP-ARO-iKO).
• To investigate the role of ADE2 in the ischemic brain using the novel GFAP-ARO-iKO model.

Main Methods:

• Generation of GFAP-ARO-iKO mice with inducible, astrocyte-specific deletion of the aromatase gene.
• Characterization of aromatase expression and E2 levels in GFAP-ARO-iKO mice after global cerebral ischemia (GCI).
• Assessment of neuroinflammation, neuronal loss, and reactive astrogliosis in the hippocampus post-GCI.

Main Results:

• GFAP-ARO-iKO mice exhibited specific depletion of astrocyte aromatase and reduced hippocampal E2 levels post-GCI.
• These mice showed impaired reactive astrogliosis and increased neuronal loss and microglial activation after GCI.
• GFAP-ARO-iKO animals remained fertile with normal brain anatomy and astrocyte morphology.

Conclusions:

• Astrocyte-derived E2 is essential for regulating reactive astrogliosis and microglial activation during ischemic brain injury.
• ADE2 exerts neuroprotective effects in the context of ischemic stroke.
• The GFAP-ARO-iKO mouse model is a valuable tool for studying ADE2's functions in the brain.