Brain-derived estrogen and neural function

Abstract

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.

Keywords: 17β-Estradiol; Aromatase; Gliosis; Memory; Neuroprotection; Neurosteroid; Sexual behavior; Synaptic plasticity.

Fig. 1.. Simplified Biosynthetic Pathway for Estrogens.

Estrogen synthesis begins with conversion of cholesterol to pregnenolone in mitochondria. Through a series of steps, pregnenolone is converted into androstenedione, which is converted into testosterone and estrone (E₁). Testosterone is then converted into 17β-estradiol (E₂) through the action of aromatase (CYP19A). As also shown, CYP19A can be inhibited by various aromatase inhibitors for research purposes and for therapies. Chemical structures were generated from the ChemSpider webpage (http://www.chemspider.com).

Fig. 2.. Partial Aromatase Gene Structure.

Tissue-specific promoters in untranslated first exons are responsible for tissue-specific transcripts of aromatase. Promoter 1.f is typically considered the brain-specific promoter; however, promoters 1.3 and 1.4 have also been reported to be expressed in the brain.

Fig. 3.. Primary aromatase inhibitors used to inhibit aromatase activity in the brain in animals and humans.

Chemical structures were generated from the ChemSpider webpage (http://www.chemspider.com).

Fig. 4.. Summary diagram illustrating multiple processes and factors that have been implicated to regulate brain aromatase.

See text for full description and discussion. BDE₂ = brain-derived 17β-estradiol. Created with BioRender.com.

Fig. 5.. Schematic illustration of the potential mechanisms underlying neuron-derived E₂ (NDE₂) regulation of synaptic plasticity.

It is proposed that neuron-derived E₂ (NDE₂) regulates synaptic plasticity via both rapid and genomic signaling mechanisms. 1) Membrane localized estrogen receptors (estrogen receptor-α and β, ERα and ERβ, and G-protein coupled estrogen receptor-1, GPER1) can bind NDE₂ and 2) the receptor bound NDE₂ then induces rapid PI3K/AKT and MEK/ERK kinase signaling, which is capable of quickly shaping synaptic plasticity. In addition, the activated intracellular kinase signaling also phosphorylates the important transcriptional factor, CREB which further translocates into nucleus to facilitate the expressions of neurotrophic factor BDNF and synaptic protein PSD95. BDNF can also regulate synaptic plasticity by coupling to the rapid intracellular kinases. Moreover, BDNF signaling activates cofilin which is required for F-actin assembly and dendritic spine formation. Intracellular ERα and ERβ act in the genomic signaling pathway by transactivating estrogen response elements (ERE) in regulated genes and promoting genes transcription. CRE = cAMP response element.

Fig. 6.. Cognitive functions regulated by neuron-derived E₂ (NDE₂) and the commonly used behavioral tests for rodent studies.

Neuron-derived E₂ (NDE₂) is critical for hippocampus-dependent spatial reference memory, which is often tested using the Barnes Maze test. Hippocampus-dependent recognition memory is another important cognitive function that is regulated by NDE₂ and which can be assessed using the Novel Object Recognition Test (NORT). In addition, NDE₂ was also demonstrated to regulate contextual, but not cued fear memory, which can be evaluated using Fearing Conditioning Test. Finally, NDE₂ is essential to prevent depressive-like behavior in female mice, which can be tested with the Forced Swimming Test.

Fig. 7.. Proposed mechanisms underlying neuron-derived E₂ (NDE₂) neuroprotection in the ischemic brain.

See text for full description. FBN-ARO-KO: forebrain neuron-specific aromatase knockout.

Fig. 8.. Proposed mechanisms underlying astrocyte-derived E₂ (ADE₂) neuroprotection in the ischemic brain.

See text for full description. GFAP-ARO-KO: astrocyte-specific aromatase knockout.