Project description:Major depressive disorder (MDD) and bipolar disorder (BD) are the most prevalent mood disorders and cause considerable burden worldwide. Compelling evidence suggests a pronounced overlap between these two diseases in clinical symptoms, treatment strategies, and genetic etiology. Here we use a BD GWAS (1822 cases and 4650 controls) and a MDD GWAS (5303 cases and 5337 controls) of Han Chinese origin to investigate their shared genetic basis, followed by exploration of the underlying mechanisms. The lead SNP in the Han Chinese meta-analysis, rs126277 at the 1q32.2 locus, also exhibited nominal associations with mood disorders as well as several sub-clinical phenotypes (e.g., mania) related to mood disorders (UK biobank samples) in European populations. Bulk tissue and single-cell eQTL studies suggest that the risk G-allele of rs126277 predicted lower SYT14 mRNA expression in human brain tissues and cells, indicating possible involvement of this gene in mood disorders. We generated mice lacking Syt14 (Syt14–/–) and mice with insufficient expression of Syt14 in the hippocampus (Syt14-KD). We found that depletion of Syt14 resulted in mania-like behaviors including hyperactivity and anti-depressive behaviors, resembling aspects of mood disorders. We also confirmed that deficiency of this gene in the hippocampus was sufficient to induce hyperactivity in the mice. RNA-sequencing analyses of the hippocampus of Syt14–/– mice revealed significant upregulation of Per1 as well as downregulation of Slc7a11 and Ptprb. Ultrastructural analyses showed significant alteration of the number of vesicles within 50 nm to the active zone and the width of synaptic cleft in the ventral hippocampus of Syt14–/– mice compared with control mice. And Syt14–/– mice exhibit aberrant glutamate signaling patterns in the hippocampus. Overall, we have identified a novel mood disorder risk gene SYT14, and confirmed its impact on mania-like behaviors and essential roles in synaptic function. While the current study provides clues for the pathological mechanisms of mood disorders, further investigations elucidating the detailed mechanisms by which SYT14 regulates mood disorders-related traits are needed.

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.

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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A pancreas–hippocampus feedback mechanism regulates circadian changes in depression-related behaviors

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