Zhongchun Liu

Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression

The dysregulation of the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis system is one of the major neuroendocrine abnormalities in major depression (MD). Many pieces of evidence supported that corticotropin-releasing hormone (CRH) play a role in the pathophysiology of major depression. In this article, whether genetic variations in the corticotropin-releasing hormone receptor1 (CRHR1) gene might be associated with increased susceptibility to major depression was studied by using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). Three SNPs were identified in CRHR1 gene and genotyped in the samples of patients diagnosed with major depression and matched controls. We observed significant allele (P=0.0008) and genotype (P=0.0002) association with rs242939, and the haplotype defined by alleles G-G-T for the represent rs1876828, rs242939 and rs242941 was significantly over-represented in major depression patients compared to controls. These results support the idea that the CRHR1 gene is likely to be involved in the genetic vulnerability for major depression.

Association study of corticotropin-releasing hormone receptor1 gene polymorphisms and antidepressant response in major depressive disorders.

Hypothalamic-pituitary-adrenal (HPA) axis appears to play a key role in the pathogenesis of major depressive disorders (MDD). Treatment of certain selective serotonin reuptake inhibitors (SSRIs) has been shown to reduce the activity of corticotropin-releasing hormone (CRH) neurons and may contribute to their therapeutic action. It has been proposed that the downregulation of CRH activity is final and common step of antidepressant treatment. In this study, we tested whether the polymorphisms of three sites (rs1876828, rs242939 and rs242941) in corticotropin-releasing hormone receptor1 (CRHR1) gene are related to 6 weeks fluoxetine antidepressant effect in 127 Han Chinese patients with MDD. The results show that the rs242941 G/G genotype and homozygous GAG haplotype of the three single-nucleotide polymorphisms (SNPs) are associated with fluoxetine therapeutic response in MDD patients of high-anxiety (HA). The results support the idea that the CRHR1 gene is likely to be involved in the antidepressant response in MDD.

Association of the brain-derived neurotrophic factor gene and bipolar disorder with early age of onset in mainland China

Several evidences have suggested that the brain-derived neurotrophic factor (BDNF) gene may be involved in the pathogenesis of bipolar disorder (BPD), but not all studies get the same result. The paper investigated two genetic polymorphisms of BDNF, C-270T and Val66Met, in a case-control design for their association with BPD. Sixty-seven patients of early age of onset and 130 patients of late age of onset were selected for study and 208 healthy individuals were used as controls. No significantly statistical differences of these two polymorphisms were found in genotypes or allele frequencies between either overall patients or late age of onset patients and normal control subjects. However, the frequency of the Val allele of the Val66Met polymorphism was found to have significantly increased in the subgroup patients with early age of onset as compared with the controls (genotype: chi(2)=6.602, d.f.=2, P=0.037; allele: chi(2)=6.223, d.f.=1, P=0.015). The study demonstrates that the BDNF C-270T and Val66Met polymorphisms are unlikely to contribute to the genetic predisposition to BPD as a whole. But Val66Met may be associated with susceptibility to the early age of onset subset of the disorder, further studies designed to explore the relationship in a larger population may be warranted.

Cytoskeletal alterations in rat hippocampus following chronic unpredictable mild stress and re-exposure to acute and chronic unpredictable mild stress

The intrinsic dynamic instability of the cytoskeletal microtubular system is essential for neuronal development and organization. The modulation of microtubule dynamics depends on the phosphorylation of neuronal microtubule-associated proteins (MAPs). Chronic unpredicted mild stress (CUMS) affects hippocampal structure and function in the rat. The aim of the present work was to investigate the possible alteration of cytoskeleton in the hippocampus of rats exposed to CUMS and re-exposed to CUMS to mimic depression and the recurrence of depression of human. We investigated the effects of CUMS, fluoxetine and re-exposure to CUMS on alpha-tubulin isoforms associated with microtubule dynamics, MAP-2 and phospho-MAP-2 in the hippocampus of rats. Our results showed that rats submitted to CUMS once showed a significant reduction in locomotion and sucrose preference which indicate a state of anhedonia. These behavioral alterations were accompanied by specific alterations in hippocampal alpha-tubulin isoforms and phospho-MAP-2 expression, indicating less microtubule dynamics and the possible mechanism. Treatment of fluoxetine could reverse CUMS-induced impairment. Moreover, there were more dramatically changes in behaviors, alpha-tubulin isoforms and phospho-MAP-2 of rats re-exposed to CUMS compared to the rats exposed to CUMS once. These findings provide evidence that rats exposed to CUMS and re-exposed to CUMS showed impairment of microtubule dynamics accompanied with the decreased level of phospho-MAP-2, providing insight into the role of cytoskeleton in the depression and recurrent of depression.

Human endogenous retroviral pol RNA and protein detected and identified in the blood of individuals with schizophrenia.

Retrovirus has been speculated as one of the potential infectious agents involved in the development of schizophrenia. Here we used nested RT-PCR to detect the RNA of HERV pol gene in blood from schizophrenic patients and normal human. We found retroviral pol genes expressed in blood from 20 of 58 (34.5%) individuals with recent-onset schizophrenia, but not from 38 normal persons (p<0.01). Sequence analysis revealed that the expressed gene was homologous to those of the human endogenous retroviral (HERV) family. The ERV9 family was the closest, with 90% homology in the gene sequence. In addition, Western blots showed that antibody against ERV9 pol protein in serum from the HERV+ schizophrenia patients, but not from control (p<0.01). Our data suggested that the transcriptional activation of certain retroviral elements might be associated with the development of schizophrenia in some patients. Further characterization of retroviral elements in subjects with schizophrenia may aid in better diagnosis and treatment of this disorder.

Glutamate transporter 1-mediated antidepressant-like effect in a rat model of chronic unpredictable stress

In recent years, more attention has been paid to the role of the glutamate transporter 1 (GLT-1, EAAT2) in major depressive disorder (MDD). However, experimental data on brain GLT-1 levels are, to some extent, inconsistent in human postmortem and animal studies. These discrepancies imply that the role of GLT-1 in the pathophysiology of MDD and the action of antidepressants remain obscure. This work was designed to study the impact of chronic unpredictable stress (CUS) for 2 sessions per day for 35 days and four weeks of fluoxetine (FLX) on depressive-like behaviors in rats, as well as the concomitant expression of the GLT-1 protein in the hippocampus. Behavioral changes were assessed by the sucrose preference and open field tests. GLT-1 levels were detected by immunohistchemistry and Western blot analysis. Our study demonstrated that the animals exposed to CUS showed depressive-like behaviors and exhibited a significant decrease in GLT-1 expression in the hippocampus. Chronic FLX treatment reversed the behavioral deficits and the CUS-induced decrease in GLT-1 levels. Taken together, our results support the reduction of GLT-1 in human postmortem studies in MDD and suggest that GLT-1 may be involved in the antidepressant activity of FLX. Our studies further support the notion that GLT-1 is an attractive candidate molecule associated with the fundamental processes of MDD and may be a potential, and novel pharmacological target for the treatment of MDD.SummaryIn recent years, more attention has been paid to the role of the glutamate transporter 1 (GLT-1, EAAT2) in major depressive disorder (MDD). However, experimental data on brain GLT-1 levels are, to some extent, inconsistent in human postmortem and animal studies. These discrepancies imply that the role of GLT-1 in the pathophysiology of MDD and the action of antidepressants remain obscure. This work was designed to study the impact of chronic unpredictable stress (CUS) for 2 sessions per day for 35 days and four weeks of fluoxetine (FLX) on depressive-like behaviors in rats, as well as the concomitant expression of the GLT-1 protein in the hippocampus. Behavioral changes were assessed by the sucrose preference and open field tests. GLT-1 levels were detected by immunohistchemistry and Western blot analysis. Our study demonstrated that the animals exposed to CUS showed depressive-like behaviors and exhibited a significant decrease in GLT-1 expression in the hippocampus. Chronic FLX treatment reversed the behavioral deficits and the CUS-induced decrease in GLT-1 levels. Taken together, our results support the reduction of GLT-1 in human postmortem studies in MDD and suggest that GLT-1 may be involved in the antidepressant activity of FLX. Our studies further support the notion that GLT-1 is an attractive candidate molecule associated with the fundamental processes of MDD and may be a potential, and novel pharmacological target for the treatment of MDD.

Histone modifications of the Crhr1 gene in a rat model of depression following chronic stress.

Multiple lines of evidence suggest a link between depression and changes in hypothalamic-pituitary-adrenal (HPA)-axis hormone dynamics, including altered regulation of the corticotrophin-releasing hormone (CRH) and its main receptor, corticotrophin-releasing hormone receptor 1 (CRHR1). However, the precise molecular mechanisms underlying depression remain poorly understood. In this study, we employed a model of depression in rats by subjecting animals to 21 days of chronic unpredictable mild stress (CUMS). Real-time PCR and western blotting were used to study the mRNA and protein expression levels of CRHR1 in the hypothalamus. In addition, chromatin immunoprecipitation assays were used to detect histone methylation at the Crhr1 gene promoter; the levels of histone H3 trimethylation at lysines 4 (H3K4) and 9 (H3K9) reflect active transcription and transcriptional repression, respectively. Rats exposed to CUMS exhibited significant reduction in locomotion and sucrose preference. These behavioral alterations were associated with elevated expression levels of CRHR1 mRNA and protein in the hypothalamus of rats in the CUMS group. We also found that the levels of H3K9 trimethylation at the Crhr1 gene promoter in the CUMS group were significantly lower than those in the control group, whereas H3K4 trimethylation levels were the same for both groups. Taken together, our findings suggest that the increase in CRHR1 expression in the hypothalamus of stressed rats correlates with a decrease in the repressive chromatin state caused by reduced H3K9 trimethylation levels. These data are the first in vivo evidence of a role for chromatin modifications in the regulation of Crhr1 gene expression in the hypothalamus, and may provide novel insight into therapeutic approaches to treat depression.

The effect of artemether on psychotic symptoms and cognitive impairment in first-episode, antipsychotic drug-naive persons with schizophrenia seropositive to Toxoplasma gondii

The objective was to evaluate the efficacy and safety of add-on artemether in first-episode, untreated people with schizophrenia, who were Toxoplasma gondii seropositive, and explore the change in T.xa0gondii antibodies during treatment. In this eight-week, double-blind, randomized, placebo-controlled trial, 100 T.xa0gondii seropositive participants with schizophrenia were randomized to either the artemether or placebo group. Participants in the artemether group received 80xa0mg artemether once per day during the second week (days 8-14) and the fourth week (days 22-28). Participants in the placebo group received identical looking placebo capsules. Psychopathology, adverse side effects and cognitive function were measured using standardized instruments. The groupxa0×xa0time interaction effects for the scores of the Positive and Negative Syndrome Scale (PANSS) subscales and performances on all cognitive components were not significant, only the main effect of group was significant. Compared to the placebo group, artemether group participants showed significantly greater reduction in the PANSS negative symptom scale (F(1,46)xa0=xa04.7, pxa0=xa00.03) and the Clinical Global Impressions Scale (F(1,96)xa0=xa06.2, pxa0=xa00.01) scores, but there were no significant differences in the PANSS positive symptom and general psychopathology scales (pxa0>xa00.05). There were also no significant differences between the two groups in performance on any of the Brief Assessment of Cognition in Schizophrenia (BACS) cognitive domains. The artemether-risperidone combination is safe and well tolerated, but artemether as an adjunct to risperidone does not appear to alleviate cognitive deficits of schizophrenia. Trial Registration Chinese Clinical Trial Register (ChiCTR) TRC-13003145.

Changes in tau phosphorylation levels in the hippocampus and frontal cortex following chronic stress

Studies have indicated that early-life or early-onset depression is associated with a 2- to 4-fold increased risk of developing Alzheimers disease (AD). In AD, aggregation of an abnormally phosphorylated form of the tau protein may be a key pathological event. Tau is known to play a major role in promoting microtubule assembly and stabilization, and in maintaining the normal morphology of neurons. Several studies have reported that stress may induce tau phosphorylation. The main aim of the present study was to investigate possible alterations in the tau protein in the hippocampus and frontal cortex of 32 male Sprague-Dawley rats exposed to chronic unpredictable mild stress (CUMS) and then re-exposed to CUMS to mimic depression and the recurrence of depression, respectively, in humans. We evaluated the effects of CUMS, fluoxetine, and CUMS re-exposure on tau and phospho-tau. Our results showed that a single exposure to CUMS caused a significant reduction in sucrose preference, indicating a state of anhedonia. The change in behavior was accompanied by specific alterations in phospho-tau protein levels, but fluoxetine treatment reversed the CUMS-induced impairments. Moreover, changes in sucrose preference and phospho-tau were more pronounced in rats re-exposed to CUMS than in those subjected to a single exposure. Our results suggest that changes in tau phosphorylation may contribute to the link between depression and AD.

Differential expression of hippocampal EphA4 and ephrinA3 in anhedonic-like behavior, stress resilience, and antidepressant drug treatment after chronic unpredicted mild stress.

Stress exposure is one of the major risk factors of depression, but the mechanism is not understood. While some individuals show resilience to stress exposure, antidepressants only partially reduce stress-induced depression in both humans and rodents. Stress could dysregulate the remodeling of neuronal dendrites and spines in hippocampus while antidepressants could recover the deficiency induced by stress. EphA4 and its ligand ephrinA3 are critical in the remodeling of neuronal dendrites and spines, but the relationship between ephrinA3/EphA4, stress-induced depression and antidepressants treatment is largely unknown. Based on a rat chronic unpredicted mild stress (CUMS) model, we investigated ephrinA3/EphA4 expression in stress susceptibility, stress resilience, treatment response and treatment resistance in rats. CUMS led to downregulation of EphA4 expression and upregulation of ephrinA3 expression in the hippocampus of stress-susceptible rats, but not in stress-resilient rats. Dysregulated EphA4 and ephrinA3 can be rescued by fluoxetine administration in drug responders, but not in fluoxetine resistant rats. These data provide insights into the potential role of EphA4 and ephrinA3 after stressor exposure, stress adaptation, fluoxetine response and drug treatment refraction.