Neuron-Derived Estrogen Is Critical for Astrocyte Activation and Neuroprotection of the Ischemic Brain

Abstract

17b-Estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but the functions of neuron-derived E2 in the ischemic brain are unclear. Here, we used a forebrain neuron-specific aromatase KO (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain and determine its roles after global cerebral ischemia. We demonstrated that ovariectomized female FBN-ARO-KO mice exhibited significantly attenuated astrocyte activation, astrocytic aromatization, and decreased hippocampal E2 levels compared with FLOX mice. Furthermore, FBN-ARO-KO mice had exacerbated neuronal damage and worse cognitive dysfunction after global cerebral ischemia. Similar results were observed in intact male mice. RNA-seq analysis revealed alterations in pathways and genes associated with astrocyte activation, neuroinflammation, and oxidative stress in FBN-ARO-KO mice. The compromised astrocyte activation in FBN-ARO-KO mice was associated with robust downregulation of the astrocyte-derived neurotrophic factors, BDNF and IGF-1, as well as the astrocytic glutamate transporter, GLT-1. Neuronal FGF2, which acts in a paracrine manner to suppress astrocyte activation, was increased in FBN-ARO-KO neurons. Interestingly, blocking FGF2 signaling by central injection of FGFR3neutralizing antibody was able to reverse the diminishment in neuroprotective astrocyte reactivity, and attenuate neuronal damage in FBN-ARO-KO mice. Moreover, in vivo E2 replacement suppressed FGF2 signaling and rescued the compromised reactive astrogliosis and cognitive deficits. Collectively, our data provide novel genetic evidence for a beneficial role of neuron-derived E2 in astrocyte activation, neuroprotection, and cognitive preservation following ischemic injury to the brain.

The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders

“…Converging lines of evidence report that estrogens, via estrogen signaling, are implicated in neuroprotection [ 111 , 112 ]. Evidence suggests their implications in synaptic plasticity, antioxidative effects, apoptosis, and protection against excitotoxicity [ 113 , 114 , 115 , 116 ].…”

Astrocyte Networks as Therapeutic Targets in Glaucomatous Neurodegeneration

“…Further, neuroprotective reactive astrocytes were first discovered in stroke models, providing a foundation for beneficial astrocyte reactivity during neurodegeneration and stress [72]. Neuroprotective astrocytes activated by ischemic stress are defined by neurotrophic factor release [73,74]. The astrocyte network expands drastically in neuroprotective astrocytes [75] and serves an important role in the neuroprotective phenotype [76].…”

Sex Differences in Recovery of Motor Function in a Rhesus Monkey Model of Cortical Injury

“…Astrocytes express estrogen receptors and produce estradiol in both males and females [80,81]. Following cortical injury, astrocytederived estradiol mediates anti-in ammatory effects through the release of neurotrophic factors, BDNF, IGF-1, and GLT-1, as the astrocytes become reactive and increase expression of ER-a receptors and glial brillary acidic protein (GFAP) [9,23,74,78,[82][83][84][85][86].…”

“…Estrogen has anti-in ammatory properties and plays a role in plasticity following injury [14][15][16][17][18][19][20][21]. Estrogen acts on ER-α and ER-β receptors expressed on neurons, astrocytes, and microglia to modulate the in ammatory response and promote repair cascades in rodents [12,17,18,20,22,23]. A large body of evidence from studies in rodents and in vitro cultures demonstrates sex differences in the immune cells and oxidative stress pathways mediating these in ammatory and repair responses after injury [12,22,[24][25][26].…”