Molecular signatures of hyperexcitability and lithium responsiveness in bipolar disorder patient neurons provides alternative therapeutic strategies
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA991455 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Bipolar Disorder (BD) is a chronic psychiatric illness affecting ~3% of the global population. It is one of the top 10 causes of disability and mortality worldwide, largely due to high suicide, cardiovascular, and metabolic comorbidity. Typically, BD has life-long presentation characterized by alternations of extreme mania and depression, associated with psychosis and self-harm. Given the complex heritability and symptoms of BD, long term clinical management of some patients remains unsatisfactory. Thus, there is a major unmet need for new clinical treatment strategies and drug options to help these patients. Lithium (Li) remains the gold standard mood stabilizer and first-line treatment for manic/depressive episodes, reducing suicide and overall mortality rates. Two major questions stand out i) how Li is effective, and ii) why for only a subset of patients? To address this, we studied the biology and lithium effects in iPSC-derived neurons from people with a known clinical and genetic profile, comparing healthy individuals, BD Li-responders, and BD Li-non responders. We combined cell imaging, electrophysiology, biochemistry, , phosphoproteomic and whole transcriptome sequencing approaches to provide mechanistic insights and guide the search for BD biomarkers and Li responsiveness.
2025-07-04 | GSE236482 | GEO
Project description:Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li responsive (LR) and Li non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/β-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/β-catenin signaling pathway by inhibiting GSK-3β and releasing β-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/β-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3β, upregulated LEF1 and Wnt/β-catenin gene targets, increased transcriptional activity of complex β-catenin/TCF/LEF1 and reduced excitability in NR neurons. Additionally, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/β-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.
2022-06-01 | GSE159487 | GEO
Project description:Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients
| PRJNA669045 | ENA
Project description:Lithium is the gold standard treatment for bipolar disorder. The goal of this study was to identify gene expression networks associated with lithium response. RNAseq data was obtained from IPSC derived neurons from lithium responders and non-responders. Focal adhesion was the network most associated with response.
2022-06-09 | GSE205422 | GEO
Project description:Bipolar disorder is a severe and heritable psychiatric disorder and affects up to 1% of the population worldwide. Lithium is recommended as first-line treatment for the maintenance treatment of bipolar-affective disorder in current guidelines, its molecular modes of action are however poorly understood. Cell models derived from bipolar patients could prove useful to gain more insight in the molecular mechanisms of bipolar disorder and the common pharmacological treatments. As primary neuronal cell lines cannot be easily derived from patients, peripheral cell models should be evaluated in their usefulness to study pathomechanisms and the mode of action of medication as well as in regard to develop biomarkers for diagnosis and treatment response.
2018-12-01 | GSE66196 | GEO
Project description:Lithium treatment is commonly used to treat bipolar disorder. However, this treatment disrupts kidney fuctionality. We used microdissected cortical collecting ducts to study proteomics and ultimately discover what changes occur in protein expression after 72-hr lithium treatment.
2019-07-01 | PXD010118 | Pride
Project description:BACKGROUND: Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and poorly understood etiology. Previous transcriptomic BD studies have had inconsistent findings due to issues such as small sample sizes and difficulty in adequately accounting for confounders like medication use. METHODS: We performed a differential expression analysis in a well-characterized BD case-control sample (Nsubjects = 480) by RNA sequencing of whole blood. We further performed co-expression network analysis, functional enrichment, and cell type decomposition, and integrated differentially expressed genes with genetic risk. RESULTS: While we observed widespread differential gene expression patterns between affected and unaffected individuals, these effects were largely linked to lithium treatment at the time of blood draw (FDR < 0.05, Ngenes = 976) rather than BD diagnosis itself (FDR < 0.05, Ngenes = 6). These lithium-associated genes were enriched for cell signaling and immune response functional annotations, among others, and were associated with neutrophil cell-type proportions, which were elevated in lithium users. Neither genes with altered expression in cases nor in lithium users were enriched for BD, schizophrenia, and depression genetic risk based on information from genome-wide association studies, nor was gene expression associated with polygenic risk scores for BD. CONCLUSIONS: These findings suggest that BD is associated with minimal changes in whole blood gene expression independent of medication use but emphasize the importance of accounting for medication use and cell type heterogeneity in psychiatric transcriptomic studies. The results of this study add to mounting evidence of lithium's cell signaling and immune-related mechanisms.
2019-10-24 | GSE124326 | GEO
Project description:Lithium is a first-line treatment for bipolar disorder, where it acts as a mood-stabilizing agent. Although its precise mechanism remains unclear, neuroimaging studies have shown that lithium accumulates in the hippocampus and that chronic use amongst bipolar disorder patients is associated with larger hippocampal volumes. Here, we tested the chronic effects of low (0.75 mM) and high (2.25 mM) doses of lithium on human hippocampal progenitor cells and used immunocytochemistry to investigate the effects of lithium on cell parameters implicated in neurogenesis. Corresponding RNA-sequencing and gene-set enrichment analyses were used to evaluate whether genes affected by lithium in our model overlap with those regulating the volume of specific layers of the dentate gyrus. We observed that high-dose lithium treatment in human hippocampal progenitors increased the generation of neuroblasts (P ≤ 0.01), neurons (P ≤ 0.01), and glia (P ≤ 0.001), alongside the expression of genes which regulate the volume of the molecular layer of the dentate gyrus. This study provides empirical support that adult hippocampal neurogenesis and gliogenesis are mechanisms that could contribute to the effects of lithium on human hippocampal volume.
2021-09-30 | GSE184930 | GEO
Project description:Metabolic alterations have been observed in the brains of patients with bipolar disorder (BD), a neuropsychiatric disorder characterized by biphasic mood episodes of mania and depression. However, the specific contributions of glial cells to these metabolic changes in BD patients remain largely unknown and have not been extensively studied. Here, we investigate the metabolic characteristics of induced astrocytes (iAstrocytes) derived from induced pluripotent stem cells of BD patients and their responses to lithium treatment. The gene expression profiles of iAstrocytes from BD patients (BD iAstrocytes) indicate dysregulation of metabolic processes in BD iAstrocytes. Compared to iAstrocytes from control subjects, BD iAstrocytes showed decreased mitochondrial respiration, increased glycolysis, and elevated lactate secretion. These changes in metabolic pathways suggest impaired mitochondrial function. Additionally, we observed reduced protein expression within the oxidative phosphorylation complex and decreased reactive oxygen species production, further supporting the impaired mitochondrial function in BD iAstrocytes. Intriguingly, BD iAstrocytes showed an accumulation of lipid droplets (LDs) in both volume and number, possibly reflecting metabolic stress-induced LD accumulation. Lithium, a commonly prescribed treatment for BD, selectively attenuated LD accumulation exclusively in BD iAstrocytes from lithium responders, while it failed to restore mitochondrial dysfunction and increased lactate secretion. Our findings provide novel insights into understanding the metabolic dysfunction in the brains of BD patients and shed light on molecular mechanisms of lithium action, particularly regarding astrocytes. The LDs in BD iAstrocytes from lithium non-responders may serve as a useful readout for drug screening to identify suitable medications for these patients.
2025-08-20 | GSE241671 | GEO
Project description:Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect
| PRJNA511612 | ENA