Genetic Deletion of Soluble Epoxide Hydroxylase Causes Anxiety-Like Behaviors in Mice

Abstract

Soluble epoxide hydrolase (sEH), an enzyme with COOH-terminal hydrolase and NH-terminal lipid phosphatase activities, is expressed in regions of the brain such as the cortex, white matter, hippocampus, substantia nigra, and striatum. sEH is involved in the regulation of cerebrovascular and neuronal function upon pathological insults. However, the physiological significance of sEH and its underlying mechanism in modulating brain function are not fully understood. In this study, we investigated the role of sEH in anxiety and potential underlying mechanisms in mice. Western blot for protein phosphorylation and expression was performed. Immunohistochemical analyses and Nissl and Golgi staining were performed for histological examination. Mouse behaviors were evaluated by open field activity, elevated plus maze, classical fear conditioning, social preference test, and Morris water maze. Our results demonstrated that the expression of sEH was upregulated during postnatal development in wild-type (WT) mice. Genetic deletion of sEH (sEH) in mice resulted in anxiety-like behavior and disrupted social preference. Increased olfactory bulb (OB) size and altered integrity of neurites were observed in sEH mice. In addition, ablation of sEH in mice decreased protein expression of tyrosine hydroxylase and reduced dopamine production in the brain. Moreover, the level of phosphorylated calmodulin kinase II (CaMKII) and glycogen synthase kinase 3 α/β (GSK3α/β) was higher in sEH mice than in WT mice. Collectively, these findings suggest that sEH is a key player in neurite outgrowth of neurons, OB development in the brain, and the development of anxiety-like behavior, by regulating the CaMKII-GSK3α/β signaling pathway.

A Distinct Metabolically Defined Central Nucleus Circuit Bidirectionally Controls Anxiety-Related Behaviors

“…2-4). One recent study showed that sEHÀ/À mice displayed anxiety-like behaviors without clear molecular and neural circuit mechanisms (Lee et al, 2019). Together, these findings demonstrated a novel role for sEH in the regulation of anxiety and might extend the function of the ARA-EET pathway in the brain.…”

“…The P450 epoxygenase pathway metabolizes ARA to hydroxyeicosatetraenoic acids (n-HETEs) and epoxyeicosatrienoic acids (EETs; Harris and Hammock, 2013;Morisseau and Hammock, 2013;Atone et al, 2020). Soluble epoxide hydrolase (sEH), a key enzyme that catalyzes the degradation of EETs, is involved in anorexia nervosa and mood disorders (Scott-Van Zeeland et al, 2014;Ren et al, 2016;Lee et al, 2019;Xiong et al, 2019). In the prefrontal cortex, sEH is mostly localized in astrocytes and regulates depressivelike behaviors (Marowsky et al, 2009;Xiong et al, 2019).…”

Soluble Epoxide Hydrolase Is Associated with Postprandial Anxiety Decrease in Healthy Adult Women

“…These differential associations are likely due to significant between-group differences in anxiety severity, variability in the postprandial increase in sEH, and sample size difference at the postprandial timepoint. Two studies using animal models have suggested that sEH may play a role in anxiety, as sEH knock-out induced anxiety-like behaviors [ 62 , 63 ]. Further work is needed to understand the link between sEH and anxiety, especially in human patients.…”

“…Previous studies using patients with depression and animal models of depression have reported elevated sEH under chronic stress and depressive conditions [ 58 , 59 , 60 ]. An sEH knock-out model and sEH downregulation have both shown anti-depressive and anxiety-modulating effects in animal models [ 59 , 60 , 61 , 62 , 63 , 64 ], implying that sEH may contribute to the etiology of depression and anxiety.…”

The Calcium/Calmodulin-Dependent Kinases II and IV as Therapeutic Targets in Neurodegenerative and Neuropsychiatric Disorders

“…Moreover, the phosphorylation of CaMKII can be regulated via various receptors or enzymes. Mice without soluble epoxide hydroxylase exhibit anxiety-like behavior as a result of the hyperphosphorylation of CaMKII and glycogen synthase kinase 3 α/β (GSK3α/β) [ 185 ]. Moreover, the decreased level of CaMKII in the striatum was observed in mice without connexin36; the protein presents in gap junctions between interneurons in several brain structures [ 186 ].…”