Abstract
Brain-derived estrogen (BDE2) produced by the enzyme aromatase has several important functions in the brain. Work using aromatase inhibitors, aromatase knockdown models, and conditional forebrain neuron-specific and astrocyte-specific aromatase knockout mouse models have provided evidence that BDE2 has a critical role in regulating synaptic function and plasticity, cognitive function, sexual differentiation and reproduction, socio-sexual behavior, and neuroprotection.
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•Aromatase is localized at synaptic and non-synaptic locations in the brain.•Neuron-derived E2 functions as a neuromodulator to regulate plasticity, memory and behavior.•Neuron-derived E2 is also neuroprotective and anti-inflammatory.•Following brain injury or ischemia, astrocytes also produce E2.•Astrocyte-derived E2 regulates gliosis, neuroinflammation, and is neuroprotective.
Although classically known as an endocrine signal produced by the ovary, 17β-estradiol (E2) is also a neurosteroid produced in neurons and astrocytes in the brain of many different species. In this review, we provide a comprehensive overview of the localization, regulation, sex differences, and physiological/pathological roles of brain-derived E2 (BDE2). Much of what we know regarding the functional roles of BDE2 has come from studies using specific inhibitors of the E2 synthesis enzyme, aromatase, as well as the recent development of conditional forebrain neuron-specific and astrocyte-specific aromatase knockout mouse models. The evidence from these studies support a critical role for neuron-derived E2 (NDE2) in the regulation of synaptic plasticity, memory, socio-sexual behavior, sexual differentiation, reproduction, injury-induced reactive gliosis, and neuroprotection. Furthermore, we review evidence that astrocyte-derived E2 (ADE2) is induced following brain injury/ischemia, and plays a key role in reactive gliosis, neuroprotection, and cognitive preservation. Finally, we conclude by discussing the key controversies and challenges in this area, as well as potential future directions for the field.
