The antidepressant and anxiolytic effect of GPER on translocator protein (TSPO) via protein kinase a (PKA) signaling in menopausal female rats

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Highlights

  • Suppression or genetic deletion of GPER could induce depressive or anxiety-like symptoms in female animals.

  • Intracerebroventricularly activation GPER by G-1 exhibited antidepressant and anxiolytic-like effects in OVX female rats.

  • G-1 alleviated hippocampal redox status in OVX female rats.

  • G-1 accelerated PKA activation and enhanced TSPO phosphorylation.

  • PKA antagonist PKI partially antagonized the anti-anxiety and anti-depression effects of G-1.

Abstract

Postmenopausal depression is mainly caused by the deprivation of ovarian hormones during menopausal transition, it is of great importance to study on the treatment that could effectively relieve symptoms of menopausal depression with fewer side effects. Activation of G-protein-coupled estrogen receptor (GPER) has long been reported to facilitate neuronal plasticity and improve cognition in animals. Meanwhile, it could participate in regulation of intracellular signaling pathways through the characteristic of GPER, ameliorate intracellular mitochondrial function and oxidative stress. However, the impact of GPER on regulating estrogen deprived-depressant and anxious behaviors is still largely unknown. Here we used the ovariectomized female rats to imitate the condition of menopause. Owing to the lateral ventricle administration of G-1 which specifically react with GPER receptor intracerebrally, Ovariectomized (OVX) female rats showed depressive- or anxiety-like phenotypes with attenuated mitochondrial function. In addition, G-1 facilitated PKA activation, which further accelerated TSPO phosphorylation and alleviated menopausal depression- and anxiety-like behaviors. Moreover, PKA inhibitor PKI could partially antagonized the anti-anxiety and anti-depression effects of G-1. Taken together, we concluded that GPER activation might exhibit antidepressant and anxiolytic effect by elevating TSPO phosphorylation via protein kinase A signaling and rescuing the redox status in menopausal female rats.

Introduction

Depression is a common mental disease characterized by mood deterioration and lack of interest (anhedonia) that seriously reduces the quality of human life [[1], [2], [3]]. Clinical evidence suggested that the incidence of depression is twice higher in women than in men [4]. In particular, more than 46% of women aged 45–55 would experience depression symptoms during or after menopause [[5], [6], [7]]. Estrogen plunge caused by ovarian disease, surgery and other factors also accelerates the risk of depression and anxiety [8] indicating the fluctuation of female hormone might be the trigger for depression. Hormone replacement therapy (HRT), via its hormone-elevating effects, represents putative antidepressant effects. However, clinical evidence revealed that HRT is handcuffed due to the risk of the deleterious events including blood clots, heart attacks, strokes and cancers related to the reproductive organs [[9], [10], [11]]. Meanwhile, HRT seems ineffective in treating depression in postmenopausal women compared to patients with onset in the menopause transition [12]. Therefore, it is of great importance to seek for treatment that could effectively relieve symptoms of menopausal depression with fewer side effects.

Large number of studies have suggested that the imbalance of oxidative stress and the decreased activity of mitochondrial enzymes such as superoxide dismutase in vivo are related to the occurrence and development of various diseases such as atherosclerosis, cardiovascular and neurodegenerative diseases. Mitochondrial function will get impaired and damaged immediately after the oxygen-free radical outrange the mitochondrial scavenging ability. Clinical evidence demonstrated that mental disorder morbidity in patients with inherited mitochondrial diseases is much higher than normal population, with approximately 54 % of patients with mitochondrial disease suffering from major depression [13]. More and more studies confirmed that mitochondrial damage and dysfunction could directly lead to mental illness and laboratory mice with hereditary mitochondrial disease exhibit gigantic susceptibility for depression and anxiety [[14], [15], [16], [17], [18]]. Since synaptic plasticity, neurogenesis and neurotransmitter network are ATP dependent processes, mitochondrial dysfunction might impede the basic information transmission between neurons which further incur depression and anxiety behaviors [[19], [20], [21]]. In fact, in neurodegenerative diseases such as Alzheimer's and Parkinson's, the susceptibility of sex differences in mitochondrial dysfunction has been confirmed [[22], [23], [24]]. Mitochondrial function in brain regions were detected after ovariectomy or orchieotectomy on animals in different genders respectively. Laboratory results showed that ovariectomy could significantly induce oxidative stress in neural mitochondria, suggesting that the loss of female hormones could generate a greater impact in neural mitochondrial function in women than that of men. Lately, more and more studies have demonstrated that the dysfunction of mitochondria in nerve cells caused by aging, depressed estrogen level and the decreased ability to resist oxidative stress might be involved in the pathogenesis of menopausal and postmenopausal depression [[25], [26], [27]]. G-protein-coupled estrogen receptor (GPER), also known as G-protein-coupled receptor 30 (GPR30) is widely distributed in the central nervous system related to emotion regulation, such as the hippocampus, cortex, hypothalamus and brainstem [[28], [29], [30], [31]]. Experiments have shown that activating GPER protected neuronal function and improved cognition in animals [32]. GPER could combine with estrogen to permit the traditional neuroprotective role of estrogen [[33], [34], [35]]. On the other hand, it could participate in the regulation of intracellular signaling pathways through the characteristic of GPER, and ameliorate intracellular mitochondrial function and oxidative stress [28,36,37]. Activation of GPER promotes the release of the second messenger cyclic adenosine phosphate cAMP, which further activates cAMP-dependent protein kinase A (PKA) to phosphorylate downstream target proteins [35,38,39]. Taken together, GPER might be a potential therapeutic target for neuroprotection and oxidative stress. Vast amounts of studies on GPER is being carried out in different organs and diseases, in OVX animal experiments, the activation of GPER was found to exert antioxidant and neurogenesis effect and further alleviate vascular damage, regulate memory and cognition and ameliorate depressive and anxiolytic symptoms [29,32,40].

TSPO (Translocator protein) located on the outer mitochondrial membrane and plays a crucial role in regulating mitochondrial calcium ions and maintaining mitochondrial membrane potential. The specific mechanisms of TSPO in central and cardiovascular system and organs with large energy demands have been deeply studied in recent years [41]. It is reported that TSPO agonists ZBD, YL-IPA08 etc. could effectively mitigate depressive- and anxiety-like behaviors, however, the mechanisms underlying is still unknown [[42], [43], [44]]. It is reported that cAMP-PKA is required to accelerate TSPO phosphorylation to ensure the outer mitochondrial membrane based pathway to control intracellular redox transients in ATP metabolism and neuroprotection [45]. Interestingly, studies have confirmed that GPER agonist G-1 could significantly activate the cAMP-PKA. Therefore, in this study, we focus on the potential protective effects of GPER-selective agonist G-1 in regulating on hippocampal mitochondrial oxidative stress and TSPO phosphorylation in menopausal depression behavior disorder in OVX female rats.

Section snippets

Animals

Sprague-Dawley female rats (200−220 g, 3-month-old) were purchased from Experimental Animal Center of the Chinese Academy. Female GPER-null mice were established from CAM-SU Genomic Resource Center (Suzhou, China), the gene information was provided in Table2 in Supplementary materials. Female mice (20−30 g, 7–week-old) were purchased from Jie Sijie J (Shanghai, China). All animals were acclimatized in our lab for 2 weeks before the experiment. Room temperature was controlled at (22 ± 1) °C

Suppression or genetic deletion of GPER could induce depressive- or anxiety-like phenotypesbehaviors in female animals

As we declared in the introduction, G-1 might play an important role in regulating mood disorders. Here we utilized GPER knock mice and GPER antagonist G-15 intracerebroventricularly injection, and evaluated the importance of GPER in depression and anxiety related mood disorder. Meanwhile, CUS and OVX female mice were set in order to confirm whether ovariectomy induced estrogen deprivation would render depression and anxiety 8-week CUS stress significantly increased the immobility time in

Discussion

Huge amount of studies had demonstrated that hormone, especially estrogen fluctuation or deprivation could lead to mood disorders such as depression and anxiety. Ovarian ablation (ovariectomy) is being widely used to study cardiovascular, skeletal, genitourinary and neurological diseases in perimenopausal or postmenopausal female [52]. It was indicated that ovariectomy which is more than 3 weeks could induce the stabilized anxiety and depressive-like behaviors in female rats according to

Contributors

J.Y.,YQ.Z.,GC.W. designed the study. J.W., HY.L., SY.S performed behavioral tests; J.W., SY.S., HJ.H. performed the molecular biology experiments; JR.Z., LF.L. undertook the statistical analysis; J.W. and J.Y. wrote the manuscript. All authors contributed to and have approved the final manuscript.

Author statement

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled.

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (81671349, 31930042 and 81774444), National Key R&D Program of China (2017YFB0403803), Development Project of Shanghai Peak Disciplines-Integrated Chinese and Western Medicine, and Project Supported by Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01), Innovative research team of high-level local universities in Shanghai and ZJ Lab.

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