Brain-derived estrogen and neural function.

Although classically known as an endocrine signal produced by the ovary, 17ß-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.

17ß-Estradiol Regulates Microglia Activation and Polarization in the Hippocampus Following Global Cerebral Ischemia.

17ß-Estradiol (E2) is a well-known neuroprotective hormone, but its role in regulation of neuroinflammation is less understood. Recently, our lab demonstrated that E2 could regulate the NLRP3 (NOD-like receptor protein 3) inflammasome pathway in the hippocampus following global cerebral ischemia (GCI). Here, we examined the ability of E2 to regulate activation and polarization of microglia phenotype in the hippocampus after global cerebral ischemia (GCI). Our in vivo study in young adult ovariectomized rats showed that exogenous low-dose E2 profoundly suppressed microglia activation and quantitatively shifted microglia from their "activated," amoeboid morphology to a "resting," ramified morphology after GCI. Further studies using M1 "proinflammatory" and M2 "anti-inflammatory" phenotype markers showed that E2 robustly suppressed the "proinflammatory" M1 phenotype, while enhancing the "anti-inflammatory" M2 microglia phenotype in the hippocampus after GCI. These effects of E2 may be mediated directly upon microglia, as E2 suppressed the M1 while enhancing the M2 microglia phenotype in LPS- (lipopolysaccharide-) activated BV2 microglia cells in vitro. E2 also correspondingly suppressed proinflammatory while enhancing anti-inflammatory cytokine gene expression in the LPS-treated BV2 microglia cells. Finally, E2 treatment abolished the LPS-induced neurotoxic effects of BV2 microglia cells upon hippocampal HT-22 neurons. Collectively, our study findings suggest a novel E2-mediated neuroprotective effect via regulation of microglia activation and promotion of the M2 "anti-inflammatory" phenotype in the brain.

NLRP3 Inflammasome Activation in the Brain after Global Cerebral Ischemia and Regulation by 17ß-Estradiol.

17ß-Estradiol (E2) is a well-known neuroprotective factor in the brain. Recently, our lab demonstrated that the neuroprotective and cognitive effects of E2 require mediation by the estrogen receptor (ER) coregulator protein and proline-, glutamic acid-, and leucine-rich protein 1 (PELP1). In the current study, we examined whether E2, acting via PELP1, can exert anti-inflammatory effects in the ovariectomized rat and mouse hippocampus to regulate NLRP3 inflammasome activation after global cerebral ischemia (GCI). Activation of the NLRP3 inflammasome pathway and expression of its downstream products, cleaved caspase-1 and IL-1ß, were robustly increased in the hippocampus after GCI, with peak levels observed at 6-7 days. Expression of P2X7 receptor, an upstream regulator of NLRP3, was also increased after GCI. E2 markedly inhibited NLRP3 inflammasome pathway activation, caspase-1, and proinflammatory cytokine production, as well as P2X7 receptor expression after GCI (at both the mRNA and protein level). Intriguingly, the ability of E2 to exert these anti-inflammatory effects was lost in PELP1 forebrain-specific knockout mice, indicating a key role for PELP1 in E2 anti-inflammatory signaling. Collectively, our study demonstrates that NLRP3 inflammasome activation and proinflammatory cytokine production are markedly increased in the hippocampus after GCI, and that E2 signaling via PELP1 can profoundly inhibit these proinflammatory effects.

Dysregulation of estrogen receptor beta (ERß), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects.

BACKGROUND: Autism spectrum disorders (ASD) are much more common in males than in females. Molecular alterations within the estrogen receptor (ER) signaling pathway may contribute to the sex difference in ASD, but the extent of such abnormalities in the brain is not known. METHODS: Postmortem middle frontal gyrus tissues (13 ASD and 13 control subjects) were used. The protein levels were examined by western blotting. The gene expression was determined by qRT-PCR. RESULTS: Gene expression analysis identified a 35% decrease in ERß mRNA expression in the middle frontal gyrus of ASD subjects. In addition, a 38% reduction in aromatase (CYP19A1) mRNA expression was observed in ASD subjects. We also found significant decreases in ER co-activators that included a 34% decrease in SRC-1, a 77% decrease in CBP, and a 52% decrease in P/CAF mRNA levels in ASD subjects relative to controls. There were no differences in the mRNA levels of TIF-2, AIB-1 (ER co-activators), ER co-repressors (SMRT and nCoR) and ERα in the middle frontal gyrus of ASD subjects as compared to controls. We observed significant correlations between ERß, CYP19A1, and co-activators in the study subjects. Immunoblot analysis further confirmed the changes in ERß and aromatase at the protein level in the control and ASD subjects. CONCLUSIONS: These results, for the first time, provide the evidence of the dysregulation of ERß and co-factors in the brain of subjects with ASD.