RESUMEN
We previously reported that neuron-specific mutant Polg1 (mitochondrial DNA polymerase) transgenic (Tg) mice exhibited bipolar disorder (BD)-like phenotypes such as periodic activity change and altered circadian rhythm. In this study, we re-evaluated two datasets resulting from DNA microarray analysis to estimate a biological pathway associated with the disorder. The gene lists were derived from the comparison between post-mortem brains of BD patients and control subjects, and from the comparison between the brains of Tg and wild-type mice. Gene ontology analysis showed that 16 categories overlapped in the altered gene expression profiles of BD patients and the mouse model. In the brains of Tg mice, 33 genes showed similar changes in the frontal cortex and hippocampus compared to wild-type mice. Among the 33 genes, SFPQ and PPIF were differentially expressed in post-mortem brains of BD patients compared to control subjects. The only gene consistently down-regulated in both patients and the mouse model was PPIF, which encodes cyclophilin D (CypD), a component of the mitochondrial permeability transition pore. A blood-brain barrier-permeable CypD inhibitor significantly improved the abnormal behaviour of Tg mice at 40 mg/kg.d. These findings collectively suggest that CypD is a promising target for a new drug for BD.
Asunto(s)
Trastorno Bipolar/tratamiento farmacológico , Ciclofilinas/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Animales , Trastorno Bipolar/metabolismo , Barrera Hematoencefálica , Peptidil-Prolil Isomerasa F , Ciclofilinas/genética , Ciclofilinas/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , ADN Polimerasa Dirigida por ADN/genética , ADN Polimerasa Dirigida por ADN/metabolismo , Femenino , Perfilación de la Expresión Génica , Hipocampo/metabolismo , Masculino , Ratones , Ratones Transgénicos , Mitocondrias/genética , Mitocondrias/metabolismo , Modelos Animales , Actividad Motora/genética , Actividad Motora/fisiología , Corteza Prefrontal/efectos de los fármacosRESUMEN
Maintenance of mitochondrial DNA (mtDNA) depends on nuclear-encoded proteins such as mtDNA polymerase (POLG), whose mutations are involved in the diseases caused by mtDNA defects including mutation and deletion. The defects in mtDNA and in intracellular Ca2+ ([Ca2+]i) homeostasis have been reported in bipolar disorder (BD). To understand the relevance of the mtDNA defects to BD, we studied transgenic (Tg) mice in which mutant POLG (mutPOLG) was expressed specifically in neurons. mtDNA defects were accumulated in the brains of mutPOLG Tg mice in an age-dependent manner and the mutant mice showed BD-like behavior. However, the molecular and cellular basis for the abnormalities has not been clarified. In this study, we investigated Ca2+ regulation by isolated mitochondria and [Ca2+]i dynamics in the neurons of mutPOLG Tg mice. Mitochondria from the mutant mice sequestered Ca2+ more rapidly, whereas Ca2+ retention capacity and membrane potential, a driving force of Ca2+ uptake, of mitochondria were unaffected. To elucidate the molecular mechanism of the altered Ca2+ uptake, we performed DNA microarray analysis and found that the expression of cyclophilin D (CyP-D), a component of the permeability transition pore, was downregulated in the brains of mutPOLG Tg mice. Cyclosporin A, an inhibitor of CyP-D, mimicked the enhanced Ca2+ uptake in mutant mice. Furthermore, G-protein-coupled receptor-mediated [Ca2+]i increase was attenuated in hippocampal neurons of the mutant mice. These findings suggest that mtDNA defects lead to enhancement of Ca2+ uptake rate via CyP-D downregulation and alter [Ca2+]i dynamics, which may be involved in the pathogenesis of BD.
Asunto(s)
Calcio/metabolismo , Ciclofilinas/metabolismo , ADN Polimerasa Dirigida por ADN/genética , Mitocondrias/metabolismo , Neuronas/fisiología , Dinámicas no Lineales , Factores de Edad , Análisis de Varianza , Animales , Peptidil-Prolil Isomerasa F , Ciclosporina/farmacología , ADN Polimerasa gamma , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Líquido Extracelular/efectos de los fármacos , Líquido Extracelular/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/citología , Técnicas In Vitro , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/farmacología , Ratones , Ratones Transgénicos , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Técnicas de Placa-Clamp/métodos , Receptores Acoplados a Proteínas G/fisiología , Estadísticas no ParamétricasRESUMEN
Recent studies indicate that long interspersed nuclear element-1 (L1) are mobilized in the genome of human neural progenitor cells and enhanced in Rett syndrome and ataxia telangiectasia. However, whether aberrant L1 retrotransposition occurs in mental disorders is unknown. Here, we report high L1 copy number in schizophrenia. Increased L1 was demonstrated in neurons from prefrontal cortex of patients and in induced pluripotent stem (iPS) cell-derived neurons containing 22q11 deletions. Whole-genome sequencing revealed brain-specific L1 insertion in patients localized preferentially to synapse- and schizophrenia-related genes. To study the mechanism of L1 transposition, we examined perinatal environmental risk factors for schizophrenia in animal models and observed an increased L1 copy number after immune activation by poly-I:C or epidermal growth factor. These findings suggest that hyperactive retrotransposition of L1 in neurons triggered by environmental and/or genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Elementos Transponibles de ADN/genética , Neuronas/metabolismo , Corteza Prefrontal/patología , Proteínas Gestacionales/genética , Esquizofrenia/patología , Síndrome de Deleción 22q11/complicaciones , Síndrome de Deleción 22q11/genética , Síndrome de Deleción 22q11/patología , Adulto , Animales , Animales Recién Nacidos , Células Cultivadas , Modelos Animales de Enfermedad , Retrovirus Endógenos/genética , Endonucleasas/genética , Endonucleasas/metabolismo , Factor de Crecimiento Epidérmico/toxicidad , Femenino , Fibroblastos/efectos de los fármacos , Ontología de Genes , Predisposición Genética a la Enfermedad , Genoma/genética , Humanos , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neuronas/efectos de los fármacos , Fosfopiruvato Hidratasa/metabolismo , Células Madre Pluripotentes/efectos de los fármacos , Poli I-C/toxicidad , Cambios Post Mortem , Embarazo , ADN Polimerasa Dirigida por ARN/genética , ADN Polimerasa Dirigida por ARN/metabolismo , Síndrome de Rett/genética , Factores de Riesgo , Esquizofrenia/inducido químicamente , Esquizofrenia/genética , TransfecciónRESUMEN
We developed transgenic (Tg) mice modeling an autosomally inherited mitochondrial disease, chronic progressive external ophthalmoplegia, patients with which sometimes have comorbid mood disorders. The mutant animals exhibited bipolar disorder-like phenotypes, such as a distorted day-night rhythm and a robust activity change with a period of 4-5 days, and the behavioral abnormalities were improved by lithium. In this study, we tested the effect of electroconvulsive stimulation (ECS) on the behavioral abnormalities of the model. Electroconvulsive therapy, which has long been used in clinical practice, provides fast-acting relief to depressive patients and drug-resistant patients. We performed long-term recordings of wheel-running activity of Tg and non-Tg mice. While recording, we administrated a train of ECS to mice, six times over two weeks or three times over a week. The treatment ameliorated the distorted day-night rhythm within three times of ECS, but it had no effect on the activity change with a period of 4-5 days in the female mice. To study the mechanism of the action, we investigated whether ECS could alter the circadian phase but found no influence on the circadian clock system. The potent and fast-acting efficacy of ECS in the mutant mice supports the predictive validity of the mice as a model of bipolar disorder. This model will be useful in developing a safe and effective alternative to lithium or electroconvulsive therapy.