RT Journal Article
SR Electronic
T1 Astrocytic Epoxyeicosatrienoic Acid Signaling in the Medial Prefrontal Cortex Modulates Depressive-like Behaviors
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3069-18
DO 10.1523/JNEUROSCI.3069-18.2019
A1 Wenchao Xiong
A1 Xiong Cao
A1 Yuanning Zeng
A1 Xihe Qin
A1 Minzhen Zhu
A1 Jing Ren
A1 Zhou Wu
A1 Qiyuan Huang
A1 Yuan Zhang
A1 Mengyao Wang
A1 Lianwan Chen
A1 Gustavo Turecki
A1 Naguib Mechawar
A1 Wenjun Chen
A1 Guoliang Yi
A1 Xinhong Zhu
YR 2019
UL http://www.jneurosci.org/content/early/2019/03/22/JNEUROSCI.3069-18.2019.abstract
AB Major depressive disorder (MDD) 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 (ARA) metabolism. Herein, we observed brain-region specific alterations of epoxyeicosatrienoic acid (EET) signaling, which is an ARA 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 medial prefrontal cortex (mPFC) of susceptible mice after chronic social defeated stress (CSDS) 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 adenosine 5′-triphosphate (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 CSDS and chronic mild stress (CMS). Together, our results highlight that EET signaling in astrocytes in the mPFC is essential for behavioral adaptation in response to psychiatric stress.SIGNIFICANCE STATEMENTAstrocytes, the most abundant glial cells of the brain, play a vital role in the pathophysiology of depression. Astrocytes secrete adenosine 5′-triphosphate (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 (EET) signaling, an ARA metabolic pathway, modulates astrocytic ATP release and the expression of depressive-like behaviors. Our work demonstrated that EET 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.