Xiong Cao

Astrocyte-derived ATP modulates depressive-like behaviors

Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the worlds population; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a Gq G protein–coupled receptor only in astrocytes to enable selective activation of astrocytic Ca2+ signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.

Behavioral animal models of depression

Depression is a chronic, recurring and potentially life-threatening illness that affects up to 20% of the population across the world. Despite its prevalence and considerable impact on human, little is known about its pathogenesis. One of the major reasons is the restricted availability of validated animal models due to the absence of consensus on the pathology and etiology of depression. Besides, some core symptoms such as depressed mood, feeling of worthlessness, and recurring thoughts of death or suicide, are impossible to be modeled on laboratory animals. Currently, the criteria for identifying animal models of depression rely on either of the 2 principles: actions of known antidepressants and responses to stress. This review mainly focuses on the most widely used animal models of depression, including learned helplessness, chronic mild stress, and social defeat paradigms. Also, the behavioral tests for screening antidepressants, such as forced swimming test and tail suspension test, are also discussed. The advantages and major drawbacks of each model are evaluated. In prospective, new techniques that will be beneficial for developing novel animal models or detecting depression are discussed.摘要抑郁症是一种慢性的、 具有高复发率的精神性疾病, 往往会危及到病人的生命。 尽맜其全球发病率高达 20%, 但人们对其病理生理机制了解甚少, 这主要归因于缺乏有效可靠的动物模型。 此外, 抑郁症的核心症状, 例如抑郁心境、 无价值感和反复出现自杀念头等, 均无法在实验动物上得以模拟。 目前, 大部分动物模型的建立 主要参照以下两个原则之一: 对于已知抗抑郁药的作用或者是对应激的反应。 本综述主要介绍目前最常用的几个 抑郁症动物模型, 包括获得性无助、 慢性温和应激和社会失败应激, 以及一些用于筛选有抗抑郁活性药物的行为 学检测方法(如强迫游泳实验和悬尾实验), 并对它们的优点与不足进行讨论。 最后, 对动物模型和行为学检测 方法的发展方向进行展望。

Intermittent Hypoxia Promotes Hippocampal Neurogenesis and Produces Antidepressant-Like Effects in Adult Rats

Increasing evidence indicates that stimulating hippocampal neurogenesis could provide novel avenues for the treatment of depression, and recent studies have shown that in vitro neurogenesis is enhanced by hypoxia. The aim of this study was to investigate the potential regulatory capacity of an intermittent hypobaric hypoxia (IH) regimen on hippocampal neurogenesis and its possible antidepressant-like effect. Here, we show that IH promotes the proliferation of endogenous neuroprogenitors leading to more newborn neurons in hippocampus in adult rats. Importantly, IH produces antidepressant-like effects in multiple animal models screening for antidepressant activity, including the forced swimming test, chronic mild stress paradigm, and novelty-suppressed feeding test. Hippocampal x-ray irradiation blocked both the neurogenic and behavioral effects of IH, indicating that IH likely produces antidepressant-like effects via promoting neurogenesis in adult hippocampus. Furthermore, IH stably enhanced the expression of BDNF in hippocampus; both the antidepressant-like effect and the enhancement of cell proliferation induced by IH were totally blocked by pharmacological and biological inhibition of BDNF–TrkB (tyrosine receptor kinase B) signaling, suggesting that the neurogenic and antidepressant-like effects of IH may involve BDNF signaling. These observations might contribute to both a better understanding of physiological responses to IH and to developing IH as a novel therapeutic approach for depression.

Fuzi polysaccharide-1 produces antidepressant-like effects in mice

Current antidepressants are clinically effective only after several weeks of administration. We show that Fuzi polysaccharide-1 (FPS), a new water-soluble polysaccharide isolated from Fuzi, which has been used to treat mood disorders in traditional Chinese medicine for centuries, increases the number of newborn cells in the dentate gyrus in adult mice, and most of these cells subsequently differentiate into new neurons. We also found that FPS administration reduces immobility in the forced swim test, and latency in the novelty suppressed-feeding test. Moreover, a 14-d regimen with FPS reverses avoidance behaviour and inhibition of hippocampal neurogenesis induced by chronic defeat stress. In contrast, imipramine, a well known antidepressant, reverses this avoidance behaviour only after 4 wk of continuous administration. Finally, acute treatment with FPS had no effect on brain monoamine levels in frontal cortex but significantly increases BDNF in the hippocampus, while the antidepressant effect and enhancement of cell proliferation induced by FPS administration were totally blocked by K252a, an inhibitor of trkB in a chronic social defeat depression model, suggesting that the neurogenic and antidepressant effects of FPS may involve BDNF signalling. In conclusion, our findings suggest that FPS could be developed as a putative antidepressant with a rapid onset of action.

Astrocytic Adenosine 5′‐Triphosphate Release Regulates the Proliferation of Neural Stem Cells in the Adult Hippocampus

Astrocytes are key components of the niche for neural stem cells (NSCs) in the adult hippocampus and play a vital role in regulating NSC proliferation and differentiation. However, the exact molecular mechanisms by which astrocytes modulate NSC proliferation have not been identified. Here, we identified adenosine 5′‐triphosphate (ATP) as a proliferative factor required for astrocyte‐mediated proliferation of NSCs in the adult hippocampus. Our results indicate that ATP is necessary and sufficient for astrocytes to promote NSC proliferation in vitro. The lack of inositol 1,4,5‐trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficient ATP release from astrocytes. This deficiency led to a dysfunction in NSC proliferation that could be rescued via the administration of exogenous ATP. Moreover, P2Y1‐mediated purinergic signaling is involved in the astrocyte promotion of NSC proliferation. As adult hippocampal neurogenesis is potentially involved in major mood disorder, our results might offer mechanistic insights into this disease. STEM Cells 2013;31:1633–1643

Soluble Epoxide Hydrolase Deficiency or Inhibition Attenuates MPTP-Induced Parkinsonism

Soluble epoxide hydrolase (sEH) inhibition has been demonstrated to have beneficial effects on various diseases, such as hypertension, diabetes, and brain ischemia. However, whether sEH inhibition has therapeutic potential in Parkinson’s disease is still unknown. In this paper, we found that sEH expression is increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-treated mice, and sEH deficiency and inhibition significantly attenuated tyrosine hydroxylase (TH)-positive cell loss and improved rotarod performance. The substrate of sEH, 14,15-epoxyeicosatrienoic acid (14,15-EET), protected TH-positive cells and alleviated the rotarod performance deficits of wild-type mice but not sEH-knockout mice. Moreover, the 14,15-EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) abolished the neuronal protective effects of sEH deficiency. In primary cultured cortical neurons, MPP+ induced significant Akt inactivation in neurons from sEH wild-type mice, and this effect was not observed in neurons from knockout mice. Our data indicate that sEH deficiency and inhibition increased 14,15-EET in MPTP-treated mice, which activated the Akt-mediated protection of TH-positive neurons and behavioral functioning. We also found that sEH deficiency attenuated TH-positive cell loss in a paraquat-induced mouse model of Parkinson’s. Our data suggest that sEH inhibition might be a powerful tool to protect dopaminergic neurons in Parkinson’s disease.

Neuronal mTORC1 is required for maintaining the nonreactive state of astrocytes

Astrocytes respond to CNS insults through reactive astrogliosis, but the underlying mechanisms are unclear. In this study, we show that inactivation of mechanistic target of rapamycin complex (mTORC1) signaling in postnatal neurons induces reactive astrogliosis in mice. Ablation of Raptor (an mTORC1-specific component) in postmitotic neurons abolished mTORC1 activity and produced neurons with smaller soma and fewer dendrites, resulting in microcephaly and aberrant behavior in adult mice. Interestingly, extensive astrogliosis without significant astrocyte proliferation and glial scar formation was observed in these mice. The inhibition of neuronal mTORC1 may activate astrogliosis by reducing neuron-derived fibroblast growth factor 2 (FGF-2), which might trigger FGF receptor signaling in astrocytes to maintain their nonreactive state, and FGF-2 injection successfully prevented astrogliosis in Raptor knock-out mice. This study demonstrates that neuronal mTORC1 inhibits reactive astrogliosis and plays an important role in CNS pathologies.

An improved Ultra-High Performance Liquid chromatography-tandem mass spectrometry method for simultaneous quantitation of cytochrome P450 metabolites of arachidonic acid in human plasma

This study aims to develop a straightforward, sensitive UHPLC-MS/MS method to quantify 15 eicosanoids derived from arachidonic acid in human plasma. Tert-Butyl methyl ether was used on the liquid-liquid extraction method and significantly reduced the expense and time. The method showed excellent linearity for all analytes, with regression coefficients higher than 0.99 over a wide range of concentrations from 0.01 ng mL-1 to 100 ng mL-1. The recovery rates were over 65.00%, and the matrix effects ranged from 8.42% to 40.00%. The limits of detection ranged from 6 pg mL-1 to 10 pg mL-1, and all of the limits of quantification were 20 - 33 pg mL-1. For the broad concentration range, the RE% for accuracy and precision were less than ± 15%. Moreover, trans-4-{4-[3-(4-Trifluoromethoxyphenyl)-ureido] cyclohexyloxy} benzoic acid (t-TUCB) pretreatment extended the window of detection for as much as 30 days. Eicosanoid signaling is altered in various neurological diseases, including pain, Alzheimers disease and major depressive disorder. Therefore, this rapid, robust quantitative profiling of 15 eicosanoids in plasma could provide a distinct eicosanoid fingerprint for precision medicine in these patients.

α2-glycine receptors modulate adult hippocampal neurogenesis and spatial memory

The α2‐glycine receptors (GlyRs) play important roles during early central nervous system development. However, these receptors’ possible involvement in neurodevelopmental events occurring in the adult brain remains to be explored. Adult hippocampal neurogenesis (AHN) is the process by which new granule cell neurons are added to the dentate gyrus (DG) throughout adulthood. In this study, we observed that hippocampal adult neural stem cells (ANSCs) express α2‐containing GlyRs. Pharmacological inhibition of GlyRs by strychnine or picrotoxin decreased the proliferation of ANSCs, both in vivo and in vitro. Mice knockout for glra2, the gene coding for the GlyR α2 subunit, were determined to display impaired AHN, and this phenomenon was accompanied by deficits in spatial memory. These results, which reveal neurodevelopmental roles for α2‐GlyRs in the adult brain, may be clinically relevant, given that a mutation in GLAR2, as well as AHN impairments, have been reported in autism spectrum disorder.