Bipolar Disorder (BD) is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression and, without treatment, 15% of patients commit suicide1. Hence, among all diseases, BD has been ranked by the WHO as a top disorder of morbidity and lost productivity2. Previous neuropathological studies have revealed a series of alterations in the brains of BD patients or animal models3, such as reduced glial cell number in the patient prefrontal cortex4, up-regulated activities of the PKA/PKC pathways5-7, and changes in dopamine/5-HT/glutamate neurotransmission systems8-11. However, the roles and causation of these changes in BD are too complex to exactly determine the pathology of the disease; none of the current BD animal models can recapitulate both the manic and depressive phenotypes or spontaneous cycling of BD simultaneously12,13. Furthermore, while some patients show remarkable improvement with lithium treatment, for yet unknown reasons, other patients are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model has been a challenge for research into BD. The development of induced pluripotent stem cell (iPSC) technology has provided such a new approach. Here, we developed a human BD iPSC model and investigated the cellular phenotypes of hippocampal dentate gyrus neurons derived from the patient iPSCs. Using patch clamp recording, somatic Ca2+ imaging and RNA-seq techniques, we found that the neurons derived from BD patients exhibited hyperactive action potential (AP) firing, up-regulated expression of PKA/PKC/AP and mitochondria-related genes. Moreover, lithium selectively reversed these alterations in the neurons of patients who responded to lithium treatment. Therefore, hyper-excitability is one endophenotype of BD that is probably achieved through enhancement in the PKA/PKC and Na+ channel signaling systems, and our BD iPSC model can be used to develop new therapies and drugs aimed at clinical treatment of this disease. Overall design: total RNAseq from neurons generated from BD patient-specific iPS cells
Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.
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View SamplesThis SuperSeries is composed of the SubSeries listed below.
Two gene co-expression modules differentiate psychotics and controls.
Sex, Age, Specimen part, Disease
View SamplesSchizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders. Associated genetic and gene expression
Two gene co-expression modules differentiate psychotics and controls.
Sex, Age, Specimen part, Disease
View SamplesSchizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders. Associated genetic and gene expression
Two gene co-expression modules differentiate psychotics and controls.
Sex, Age, Specimen part, Disease
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature.
Sex
View SamplesGenome-wide analysis of transcriptional profiles in children <17 years of age with inflammatory diseases, bacterial or viral infections or with clinical features suggestive of infection.
Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature.
Sex
View SamplesGenome-wide analysis of transcriptional profiles in children <17 years of age with inflammatory diseases, bacterial or viral infections or with clinical features suggestive of infection.
Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature.
Sex
View SamplesGenome-wide analysis of transcriptional profiles in children <17 years of age with inflammatory diseases, bacterial or viral infections or with clinical features suggestive of infection.
Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature.
Sex
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance.
Specimen part, Disease
View SamplesPersistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) relates to inferior survival in multiple myeloma (MM). MRD PCs are therefore a minor clone able to recapitulate the initial tumor burden at relapse and accordingly, its characterization may represent a unique model to understand chemoresistance; unfortunately, the MRD clone has never been biologically investigated. Here, we compared the antigenic profile of MRD vs. diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study, and showed that the MRD clone is enriched by cells over-expressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4) and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs. diagnostic PCs showed identical copy number alterations (CNAs) in 3/8 cases, 2 patients with linear acquisition of additional CNAs in MRD clonal PCs, and 3 cases with variable acquisition and loss of CNAs over time. The MRD clone showed significant downregulation of genes particularly related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and identifies chemoresistant PCs in vitro. Together, we show that therapy-induced clonal selection is already present at the MRD stage, in which chemoresistant PCs show a specific phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles.
Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance.
Specimen part, Disease
View Samples