Xin-Hong Zhu

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。

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

Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling

Ion channels are essential for the regulation of neuronal functions. The significance of plasma membrane, mitochondrial, endoplasmic reticulum and lysosomal ion channels in the regulation of Ca2+ is well established. In contrast, surprisingly little is known about the function of ion channels on the nuclear envelope (NE). Here we demonstrate the presence of functional large-conductance, calcium-activated potassium channels (BK channels) on the NE of rodent hippocampal neurons. Functionally, blockade of nuclear BK channels (nBK channels) induces NE-derived Ca2+ release, nucleoplasmic Ca2+ elevation and cyclic AMP response element binding protein (CREB)-dependent transcription. More importantly, blockade of nBK channels regulates nuclear Ca2+–sensitive gene expression and promotes dendritic arborization in a nuclear Ca2+–dependent manner. These results suggest that the nBK channel functions as a molecular link between neuronal activity and nuclear Ca2+ to convey signals from synapse to nucleus and is a new modulator, operating at the NE, of synaptic activity–dependent neuronal functions.

Mitochondrial BNIP3 upregulation precedes endonuclease G translocation in hippocampal neuronal death following oxygen-glucose deprivation

BackgroundCaspase-independent apoptotic pathways are suggested as a mechanism for the delayed neuronal death following ischemic insult. However, the underlying signalling mechanisms are largely unknown. Recent studies imply the involvement of several mitochondrial proteins, including endonuclease G (EndoG) and Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP3), in the pathway of non-neuronal cells.ResultsIn this report, using western blot analysis and immunocytochemistry, we found that EndoG upregulates and translocates from mitochondria to nucleus in a time-dependent manner in cultured hippocampal neurons following oxygen-glucose deprivation (OGD). Moreover, the translocation of EndoG occurs hours before the observable nuclear pyknosis. Importantly, the mitochondrial upregulation of BNIP3 precedes the translocation of EndoG. Forced expression of BNIP3 increases the nuclear translocation of EndoG and neuronal death while knockdown of BNIP3 decreases the OGD-induced nuclear translocation of EndoG and neuronal death.ConclusionThese results suggest that BNIP3 and EndoG play important roles in hippocampal neuronal apoptosis following ischemia, and mitochondrial BNIP3 is a signal protein upstream of EndoG that can induce neuronal death.

Neuroprotective effects of Xiao-Xu-Ming decoction against ischemic neuronal injury in vivo and in vitro

ETHNOPHARMACOLOGICAL RELEVANCE Xiao-Xu-Ming decoction (XXMD) has long been employed clinically to treat stroke in traditional Chinese Medicine. AIM OF THE STUDY To investigate the neuroprotective effects of XXMD in vivo and in vitro stroke models and determine involved mechanisms. MATERIALS AND METHODS Two models (four-vessel occlusion in adult Wistar rats and oxygen-glucose deprivation primary cultured neurons) were employed to mimic ischemia-reperfusion damage, in vivo and in vitro, respectively. The effects of XXMD were investigated with respect to neuronal damage, activity of caspase-3 and expression of Bcl-2 in CA1 region of hippocampus after ischemia. The cognitive ability was measured 7 days after ischemia/reperfusion by using Morris water maze. RESULTS Oral administration of XXMD significantly increased the density of neurons that survived in the CA1 region of hippocampus on the 3rd and 7th day after transient global ischemia was induced in a dose-dependent manner. XXMD ameliorated severe deficiencies in spatial cognitive performance induced by transient global ischemia. Inhibition of caspase-3 activity and up-regulation of Bcl-2 expression were induced in the high dose of XXMD-treated rats after ischemia. In oxygen-glucose deprivation model, both XXMD extract and drug-containing serum prepared from blood of high dose of XXMD-treated rats inhibited apoptotic neuronal death at 24h after reoxygenation. CONCLUSIONS Our results clearly demonstrated that XXMD is neuroprotective and appears to influence deleterious pathological processes that are activated after the onset of ischemia.

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.

miR-124 and miR-9 mediated downregulation of HDAC5 promotes neurite development through activating MEF2C-GPM6A pathway.

The class IIa histone deacetylases (HDACs) play important roles in the central nervous system during diverse biological processes such as synaptic plasticity, axon regeneration, cell apoptosis, and neural differentiation. Although it is known that HDAC5 regulates neuronal differentiation, neither the physiological function nor the regulation of HDAC5 in neuronal differentiation is clear. Here, we identify HDAC5 as an inhibitor of neurite elongation and show that HDAC5 is regulated by the brain enriched microRNA miR‐124 and miR‐9. We discover that HDAC5 inhibits neurite extension both in differentiated P19 cells and primary neurons. We also show that the neuronal membrane glycoprotein GPM6A (M6a) is a direct target gene of HDAC5 regulated transcriptional factor MEF2C. HDAC5 inhibits neurite elongation, acting at least partially via a MEF2C/M6a signaling pathway. We also confirmed the miR‐124/miR‐9 regulated HDAC5‐MEF2C‐M6a pathway regulates neurite development in primary neurons. Thus, HDAC5 emerges as a cellular conductor of MEF2C and M6a activity and is regulated by miR‐124 and miR‐9 to control neurite development.

Neuregulin 1 protects against ischemic brain injury via ErbB4 receptors by increasing GABAergic transmission

Identifying novel neuroprotectants that can halt or even reverse the effects of stroke is of interest to both clinicians and scientists. Neuregulin 1 (NRG1) is an effective neuroprotectant, but its molecular mechanisms are largely unclear. In this study, NRG1 rescued cortical neurons from oxygen-glucose deprivation (OGD) model, but the effect was blocked by neutralizing NRG1 and ErbB4 inhibition. In addition, γ-Aminobutyric acid (GABA) receptor agonists had no synergistic effect with NRG1, and the neuroprotective effect of NRG1 against OGD was partly blocked by GABA receptor antagonists. Importantly, NRG1 neuroprotection against brain ischemia was abolished in the mice with specific deletion of ErbB4 in parvalbumin (PV)-positive interneurons. In summary, NRG1 protects against ischemic brain injury via ErbB4 receptors by enhancing GABAergic transmission.