MicroRNA-502-3p regulates GABAergic synapse function in hippocampal neurons

Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's disease-related dementia.Our previous study identified the upregulation of microRNA-502-3p(miR-502-3p)and downregulation of GABA type A receptor subunitα-1 in Alzheimer's disease synapses.This study investigated a new molecular relationship between miR-502-3p and GABAergic synapse function.In vitro studies were perfo rmed using the mouse hippocampal neuronal cell line HT22 and miR-502-3p agomiRs and antagomiRs.In silico analysis identified multiple binding sites of miR-502-3p at GABA type A receptor subunitα-1 mRNA.Luciferase assay confirmed that miR-502-3p targets the GABA type A receptor subunitα-1 gene and suppresses the luciferase activity.Furthermore,quantitative reve rse transcription-polymerase chain reaction,miRNA in situ hybridization,immunoblotting,and immunostaining analysis confirmed that overexpression of miR-502-3p reduced the GABA type A receptor subunitα-1 level,while suppression of miR-502-3p increased the level of GABA type A receptor subunitα-1 protein.Notably,as a result of the overexpression of miR-502-3p,cell viability was found to be reduced,and the population of necrotic cells was found to be increased.The whole cell patch-clamp analysis of human-GABA receptor A-α1/β3/γ2L human embryonic kidney(HEK)recombinant cell line also showed that overexpression of miR-502-3p reduced the GABA current and overall GABA function,suggesting a negative correlation between miR-502-3p levels and GABAergic synapse function.Additionally,the levels of proteins associated with Alzheimer s disease were high with miR-502-3p overexpression and reduced with miR-502-3p suppression.The present study provides insight into the molecular mechanism of regulation of GABAergic synapses by miR-502-3p.We propose that micro-RNA,in particular miR-502-3p,could be a potential therapeutic to rget to modulate GABAergic synapse function in neurological disorders,including Alzheimer's disease and Alzheimer's diseaserelated dementia.

低氧环境下听觉习服中GABAergic synapse的调控研究

目的:探索GABAergic synapse是否参与低氧环境下听觉习服的调控。方法:将8周龄Wistar大鼠随机分为移居高原30天组、移居高原60天组,提取两组大鼠耳蜗组织RNA,用全转录测序法筛选两组间大鼠耳蜗RNA的差异表达基因进行KEGG、GO富集分析。结果:转录组测序筛选差异表达基因结果显示,移居高原60天组与移居高原30天组的耳蜗组织mRNA比较,共筛选到上调基因166个(P<0.05,FC>2),下调基因83个(P<0.05,FC>2),其中GABAergic synapse通路的上调基因为:Gabra1、Gabra2、Gabra3,下调基因为Cacna1s;KEGG分析发现,γ氨基丁酸能突触(GABAergic synapse)通路在听觉习服中作用显著(P<0.05);GO分析结果显示:γ氨基丁酸A受体复合物(GABA-A receptor complex)(P<0.01)、γ氨基丁酸氯离子门控通道活性(GABA-gated chloride ion channel activity)(P<0.01)等功能被富集。结论:GABAergic synapse信号传导途径参与了低氧环境下听觉习服的过程。

Delineation of biomarkers and molecular pathways of residual effects of fluoxetine treatment in juvenile rhesus monkeys by proteomic profiling

Fluoxetine(Prozac^(TM))is the only antidepressant approved by the US Food and Drug Administration(FDA)for the treatment of major depressive disorder(MDD)in children.Despite its considerable efficacy as a selective serotonin reuptake inhibitor,the possible long-term effects of fluoxetine on brain development in children are poorly understood.In the current study,we aimed to delineate molecular mechanisms and protein biomarkers in the brains of juvenile rhesus macaques(Macaca mulatta)one year after the discontinuation of fluoxetine treatment using proteomic and phosphoproteomic profiling.We identified several differences in protein expression and phosphorylation in the dorsolateral prefrontal cortex(DLPFC)and cingulate cortex(CC)that correlated with impulsivity in animals,suggesting that the GABAergic synapse pathway may be affected by fluoxetine treatment.Biomarkers in combination with the identified pathways contribute to a better understanding of the mechanisms underlying the chronic effects of fluoxetine after discontinuation in children.

Antagonistic interaction between caffeine and ketamine in zebrafish: Implications for aquatic toxicity

The coexistence of caffeine(CF)and ketamine(KET)in surface waters across Asia has been widely reported.Previous studies have implied that CF and KET may share a mechanism of action.However,the combined toxicity of these two chemicals on aquatic organisms remains unclear at environmental levels,and the underlying mechanisms are not well understood.Here we demonstrate that KET antagonizes the adverse effects of CF on zebrafish larvae by modulating the gamma-aminobutyric acid(GABA)ergic synapse pathway.Specifically,KET(10e250 ng L^(-1))ameliorates the locomotor hyperactivity and impaired circadian rhythms in zebrafish larvae induced by 2 mg L^(-1) of CF,showing a dose-dependent relationship.Additionally,the developmental abnormalities in zebrafish larvae exposed to CF are mitigated by KET,with an incidence rate reduced from 26.7%to 6.7%.The competition between CF and KET for binding sites on the GABA-A receptor(in situ and in silico)elucidates the antagonistic interactions between the two chemicals.Following a seven-day recovery period,the adverse outcomes of CF exposure persist in the fish,whereas the changes observed in the CFþKET groups are significantly alleviated,especially with KET at 10 ng L^(-1).Based on these results,it is imperative to further assess the environmental risks associated with CF and KET co-pollution.This pilot study underscores the utility of systems toxicology approaches in estimating the combined toxicity of environmental chemicals on aquatic organisms.Moreover,the nighttime behavioral functions of fish could serve as a sensitive biomarker for evaluating the toxicity of psychoactive substances.

The role of Down syndrome cell adhesion molecule in Down syndrome

Down syndrome(DS)is caused by the presence of an extra copy of the entire or a portion of human chromosome 21(HSA21).This genomic alteration leads to elevated expression of numerous HSA21 genes,resulting in a variety of health issues in individuals with DS.Among the genes located in the DS“critical region”of HSA21,Down syndrome cell adhesion molecule(DSCAM)plays an important role in neuronal development.There is a growing body of evidence underscoring DSCAM’s involvement in various DS-related disorders.This review aims to provide a concise overview of the established functions of DSCAM,with a particular focus on its implications in DS.We delve into the roles that DSCAM plays in DS-associated diseases.In the concluding section of this review,we explore prospective avenues for future research to further unravel DSCAM’s role in DS and opportunities for therapeutic treatments.