Astrocytic Epoxyeicosatrienoic Acid Signaling in the Medial Prefrontal Cortex Modulates Depressive-like Behaviors

Abstract

Major depressive disorder is the most common mental illness. Mounting evidence indicates that astrocytes play a crucial role in the pathophysiology of depression; however, the underlying molecular mechanisms remain elusive. Compared with other neuronal cell types, astrocytes are enriched for arachidonic acid metabolism. Herein, we observed brain-region-specific alterations of epoxyeicosatrienoic acid (EET) signaling, which is an arachidonic acid metabolic pathway, in both a mouse model of depression and postmortem samples from patients with depression. The enzymatic activity of soluble epoxide hydrolase (sEH), the key enzyme in EET signaling, was selectively increased in the mPFC of susceptible mice after chronic social defeated stress and was negatively correlated with the social interaction ratio, which is an indicator of depressive-like behavior. The specific deletion of Ephx2 (encode sEH) in adult astrocytes induced resilience to stress, whereas the impaired EET signaling in the mPFC evoked depressive-like behaviors in response to stress. sEH was mainly expressed on lysosomes of astrocytes. Using pharmacological and genetic approaches performed on C57BL/6J background adult male mice, we found that EET signaling modulated astrocytic ATP release in vitro and in vivo. Moreover, astrocytic ATP release was required for the antidepressant-like effect of Ephx2 deletion in adult astrocytes. In addition, sEH inhibitors produced rapid antidepressant-like effects in multiple animal models of depression, including chronic social defeated stress and chronic mild stress. Together, our results highlight that EET signaling in astrocytes in the mPFC is essential for behavioral adaptation in response to psychiatric stress.Astrocytes, the most abundant glial cells of the brain, play a vital role in the pathophysiology of depression. Astrocytes secrete adenosine ATP, which modulates depressive-like behaviors. Notably, astrocytes are enriched for arachidonic acid metabolism. In the present study, we explored the hypothesis that epoxyeicosatrienoic acid signaling, an arachidonic acid metabolic pathway, modulates astrocytic ATP release and the expression of depressive-like behaviors. Our work demonstrated that epoxyeicosatrienoic acid signaling in astrocytes in the mPFC is essential for behavioral homeostatic adaptation in response to stress, and the extent of astrocyte functioning is greater than expected based on earlier reports. Figure 1. ARA metabolic pathways in the mouse model and patients with MDD. A, Schematic representation of the ARA metabolic pathway. PLA2 enzymes are crucial for transferring esterified ARA to free ARA for metabolism. Three members of the PLA2 superfamily have been implicated most strongly in eicosanoid production, including cytosolic calcium-dependent PLAs [group ( G) 4a-c], cytosolic calcium-independent PLA2 (G6 ), and secreted PLA2 (G2a, b, e and G10). Adipose-specific PLA2 is G16. The free ARA can be converted to eicosanoids via three pathways: the LOX, COX, and CYP. B, Identification of susceptible ...

14,15-Epoxyeicosatrienoic Acid Alleviates Pathology in a Mouse Model of Alzheimer's Disease

“…EETs have vasodilatory and anti-inflammatory actions, and pathophysiologic features of AD include early vascular damage and progressive inflammation (De Strooper and Karran, 2016;Wu et al, 2017). We recently reported that, in the brain, sEH is mainly localized in the lysosomes of astrocytes and plays an important role in regulating astrocyte function (Qin et al, 2019;Xiong et al, 2019). In the present study, we tested the hypothesis that sEH contributes to the pathophysiology of AD through the modulation of Ab metabolism in astrocytes.…”

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“…A recent study has demonstrated that lipid signaling in PFC astrocytes modulates depressive-like behaviors [ 38 ]. Producing an increase in epoxyeicosatrienoic acid (EET) by injecting a mixture of inhibitors hydrolyzing EET into the PFC reduces CSDS-elicited immobility in FST, whereas the infusion of a selective antagonist of EET increases immobility in the same test.…”

The Ghrelin/Growth Hormone Secretagogue Receptor System Is Involved in the Rapid and Sustained Antidepressant-Like Effect of Paeoniflorin

“…All the experiments were conducted following the Chinese Council on Animal Care guidelines. All the behavioral tests were conducted following the procedures established in our laboratory, with some modifications ( Cao et al, 2013 ; Qin et al, 2019 ; Wang et al, 2019 ; Xiong et al, 2019 ).…”

“…The methodology for the CMS paradigm was as previously described ( Cao et al, 2013 ; Qin et al, 2019 ; Xiong et al, 2019 ). Mice were briefly individually caged and habituated to water or a 1% sucrose solution for the assessment of the baseline sucrose preference.…”