Gut microbiota from NLRP3-deficient mice ameliorates depressive-like behaviors by regulating astrocyte dysfunction via circHIPK2.
Zhang Yuan,Huang Rongrong,Cheng Mengjing,Wang Lirui,Chao Jie,Li Junxu,Zheng Peng,Xie Peng,Zhang Zhijun,Yao Honghong
BACKGROUND:Inflammasomes have been found to interact with the gut microbiota, and this effect is associated with depression, but the mechanisms underlying this interaction have not been elucidated in detail. RESULTS:The locomotor activity of NLRP3 KO mice was significantly greater than that of their WT littermates, while cohousing and transplantation of the NLRP3 KO gut microbiota avoid the effects of NLRP3 KO on the general locomotor activity at baseline. Meanwhile, transplantation of the NLRP3 KO microbiota alleviated the CUS-induced depressive-like behaviors. The compositions of the gut microbiota in NLRP3 KO mice and WT mice were significantly different in terms of the relative abundance of Firmicutes, Proteobacteria, and Bacteroidetes. Fecal microbiota transplantation (FMT) from NLRP3 KO mice significantly ameliorated the depressive-like behavior induced by chronic unpredictable stress (CUS) in recipient mice. Given the correlation between circular RNA HIPK2 (circHIPK2) and depression and the observation that the level of circHIPK2 expression was significantly increased in CUS-treated mice compared with that in the control group, further experiments were performed. FMT significantly ameliorated astrocyte dysfunction in recipient mice treated with CUS via inhibition of circHIPK2 expression. CONCLUSIONS:Our study illustrates the involvement of the gut microbiota-circHIPK2-astrocyte axis in depression, providing translational evidence that transplantation of the gut microbiota from NLRP3 KO mice may serve as a novel therapeutic strategy for depression.
CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination.
Zhang Yuan,Du Longfei,Bai Ying,Han Bing,He Cancan,Gong Liang,Huang Rongrong,Shen Ling,Chao Jie,Liu Pei,Zhang Hongxing,Zhang Haisan,Gu Ling,Li Junxu,Hu Gang,Xie Chunming,Zhang Zhijun,Yao Honghong
Circular RNAs (circRNAs), highly expressed in the central nervous system, are involved in various regulatory processes and implicated in some pathophysiology. However, the potential role of circRNAs in psychiatric diseases, particularly major depressive disorder (MDD), remains largely unknown. Here, we demonstrated that circular RNA DYM (circDYM) levels were significantly decreased both in the peripheral blood of patients with MDD and in the two depressive-like mouse models: the chronic unpredictable stress (CUS) and lipopolysaccharide (LPS) models. Restoration of circDYM expression significantly attenuated depressive-like behavior and inhibited microglial activation induced by CUS or LPS treatment. Further examination indicated that circDYM functions as an endogenous microRNA-9 (miR-9) sponge to inhibit miR-9 activity, which results in a downstream increase of target-HECT domain E3 ubiquitin protein ligase 1 (HECTD1) expression, an increase of HSP90 ubiquitination, and a consequent decrease of microglial activation. Taken together, the results of our study demonstrate the involvement of circDYM and its coupling mechanism in depression, providing translational evidence that circDYM may be a novel therapeutic target for depression.
meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes.
Ciuculete Diana M,Voisin Sarah,Kular Lara,Jonsson Jörgen,Rask-Andersen Mathias,Mwinyi Jessica,Schiöth Helgi B
BACKGROUND:Little is known about how genetics and epigenetics interplay in depression. Evidence suggests that genetic variants may change vulnerability to depression by modulating DNA methylation (DNAm) and non-coding RNA (ncRNA) levels. Therefore, the aim of the study was to investigate the effect of the genetic variation, previously identified in the largest genome-wide association study for depression, on proximal DNAm and ncRNA levels. RESULTS:We performed DNAm quantitative trait locus (meQTL) analysis in two independent cohorts (total n = 435 healthy individuals), testing associations between 102 single-nucleotide polymorphisms (SNPs) and DNAm levels in whole blood. We identified and replicated 64 SNP-CpG pairs (p < 0.05) with meQTL effect. Lower DNAm at cg02098413 located in the HACE1 promoter conferred by the risk allele (C allele) at rs1933802 was associated with higher risk for depression (p = 0.014, DNAm = 2.3%). In 1202 CD14+ cells sorted from blood, DNAm at cg02088412 positively correlated with HACE1 mRNA expression. Investigation in postmortem brain tissue of adults diagnosed with major depressive disorder (MDD) indicated 1% higher DNAm at cg02098413 in neurons and lower HACE1 mRNA expression in CA1 hippocampus of MDD patients compared with healthy controls (p = 0.008 and 0.012, respectively). Expression QTL analysis in blood of 74 adolescent revealed that hsa-miR-3664-5p was associated with rs7117514 (SHANK2) (p = 0.015, mRNA difference = 5.2%). Gene ontology analysis of the miRNA target genes highlighted implication in neuronal processes. CONCLUSIONS:Collectively, our findings from a multi-tissue (blood and brain) and multi-layered (genetic, epigenetic, transcriptomic) approach suggest that genetic factors may influence depression by modulating DNAm and miRNA levels. Alterations at HACE1 and SHANK2 loci imply potential mechanisms, such as oxidative stress in the brain, underlying depression. Our results deepened the knowledge of molecular mechanisms in depression and suggest new epigenetic targets that should be further evaluated.
Stress-induced perinatal and transgenerational epigenetic programming of brain development and mental health.
Babenko Olena,Kovalchuk Igor,Metz Gerlinde A S
Neuroscience and biobehavioral reviews
Research efforts during the past decades have provided intriguing evidence suggesting that stressful experiences during pregnancy exert long-term consequences on the future mental wellbeing of both the mother and her baby. Recent human epidemiological and animal studies indicate that stressful experiences in utero or during early life may increase the risk of neurological and psychiatric disorders, arguably via altered epigenetic regulation. Epigenetic mechanisms, such as miRNA expression, DNA methylation, and histone modifications are prone to changes in response to stressful experiences and hostile environmental factors. Altered epigenetic regulation may potentially influence fetal endocrine programming and brain development across several generations. Only recently, however, more attention has been paid to possible transgenerational effects of stress. In this review we discuss the evidence of transgenerational epigenetic inheritance of stress exposure in human studies and animal models. We highlight the complex interplay between prenatal stress exposure, associated changes in miRNA expression and DNA methylation in placenta and brain and possible links to greater risks of schizophrenia, attention deficit hyperactivity disorder, autism, anxiety- or depression-related disorders later in life. Based on existing evidence, we propose that prenatal stress, through the generation of epigenetic alterations, becomes one of the most powerful influences on mental health in later life. The consideration of ancestral and prenatal stress effects on lifetime health trajectories is critical for improving strategies that support healthy development and successful aging.
The importance of long non-coding RNAs in neuropsychiatric disorders.
Hosseini Ebrahim,Bagheri-Hosseinabadi Zahra,De Toma Ilario,Jafarisani Moslem,Sadeghi Iman
Molecular aspects of medicine
In the last decade, transcriptome analyses have discovered thousands of long non-coding RNAs (lncRNAs) which are assumed as a fundamental part of the gene regulatory networks in the cell. Intriguingly, lncRNAs are abundantly enriched in the brain, displaying elaborate spatiotemporal expression profiles and modulation. They diversely participate in the delicate regulation of the central nervous system (CNS) development including self-renewal maintenance, cell fate decision, synapse plasticity, synaptogenesis and memory formation. Moreover, lncRNAs have vastly demonstrated correlations with mental illnesses such as neuropsychiatric disorders (NPDs), implying the vital jobs of these yet poorly-understood transcripts. Here, we underlie the accumulating evidence for the significance of lncRNAs in neural networks and their impairment in several NPDs including autism spectrum disorder (ASD), schizophrenia (SZ), intellectual disability (ID), major depressive disorder (MDD), Rett syndrome (RTT) and others.