State- and trait-specific gene expression in euthymia and mania
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE46416 | GEO | 2014/09/04
SECONDARY ACCESSION(S): PRJNA200303
REPOSITORIES: GEO
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Project description:Gene expression profiles of bipolar disorder (BD) patients were assessed during both a manic and a euthymic phase and compared both intra-individually, and with the gene expression profiles of controls. 11 BD patients were assessed in their manic as well as in their euthymic phase. Comparison of gene expression BD euthymic vs. controls, BD manic vs. controls, and intra-patient comparison BD euthymic vs. BD manic.
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Project description: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. total RNAseq from neurons generated from BD patient-specific iPS cells
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Project description: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.
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Project description:Bipolar disorder (BD) (1% of the general population) is a major affective disorder characterized by recurrent manic and depressive episodes and associated with considerable burden and costs. Lithium (Li) is the first line treatment for relapse prevention in bipolar disorders with many patients who remain asymptomatic for several years (even decades). In addition, it is the only psychoactive drug that has demonstrated efficacy in suicide prevention. However a large proportion of patients is experiencing very high relapse rates (overall between 70 and 80% relapse, 2 years after a major episode). Li mechanism of action is rather complex and still not fully understood despite extensive studies. In order to explore potential lithium effects on global gene and miRNAs expression, we initiated a study in cell-lines from excellent responders (ER) and non-responders (NR) bipolar patients Briefly, long-term treatment response to lithium was evaluated using a validated scale “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” , also known as the Alda scale. In our sample we analyzed dichotomous phenotypes for lithium response: patients with total score (TS) higher or equal to 7, characterized as ER; and patients with TS lower than 2, characterized as NR according to the literature.
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Project description:Bipolar disorder (BD) (1% of the general population) is a major affective disorder characterized by recurrent manic and depressive episodes and associated with considerable burden and costs. Lithium (Li) is the first line treatment for relapse prevention in bipolar disorders with many patients who remain asymptomatic for several years (even decades). In addition, it is the only psychoactive drug that has demonstrated efficacy in suicide prevention. However a large proportion of patients is experiencing very high relapse rates (overall between 70 and 80% relapse, 2 years after a major episode). Li mechanism of action is rather complex and still not fully understood despite extensive studies. In order to explore potential lithium effects on global gene and miRNAs expression, we initiated a study in cell-lines from excellent responders (ER) and non-responders (NR) bipolar patients Briefly, long-term treatment response to lithium was evaluated using a validated scale “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” , also known as the Alda scale. In our sample we analyzed dichotomous phenotypes for lithium response: patients with total score (TS) higher or equal to 7, characterized as ER; and patients with TS lower than 2, characterized as NR according to the literature.
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