Neuronal Activity-Induced Sterol Regulatory Element Binding Protein-1 (SREBP1) is Disrupted in Dysbindin-Null Mice-Potential Link to Cognitive Impairment in Schizophrenia
| Autor: | Greg N. Carlson, Mary F. McMullen, Sookhee Bang, Hala Kazi, Mei Xuan Ho, Konrad Talbot, Yong Chen, Sangwon F. Kim, Steven E. Arnold, Wei-Yi Ong |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male Population Neuroscience (miscellaneous) Epigenetics of schizophrenia PC12 Cells Article 03 medical and health sciences Cellular and Molecular Neuroscience Mice Random Allocation 0302 clinical medicine Organ Culture Techniques medicine Animals Humans Cognitive Dysfunction Gene Regulatory Networks Longitudinal Studies education Aged Aged 80 and over Mice Knockout Neurons education.field_of_study Arc (protein) Dysbindin medicine.disease Sterol regulatory element-binding protein Rats 030104 developmental biology Neurology Schizophrenia Knockout mouse Sterol Regulatory Element Binding Protein 1 Female Schizophrenic Psychology Psychology Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Molecular neurobiology. 54(3) |
| ISSN: | 1559-1182 |
| Popis: | Schizophrenia is a chronic deliberating neuropsychiatric disorder that affects about 1% of the population. Dystrobrevin-binding protein 1 (DTNBP1 or dysbindin) is one of Research Domain Constructs (RDoC) associated with cognition and is significantly reduced in the brain of schizophrenia patients. To further understand the molecular underpinnings of pathogenesis of schizophrenia, we have performed microarray analyses of the hippocampi from dysbindin knockout mice, and found that genes involved in lipogenic pathway are suppressed. Moreover, we uncovered that maturation of a master transcriptional regulator for lipid synthesis, sterol regulatory element binding protein-1 (SREBP1) is induced by neuronal activity, and is required for the induction of the immediate early gene protein ARC (activity-regulated cytoskeleton-associated protein), necessary for synaptic plasticity and memory. We revealed that nuclear SREBP1 is dramatically reduced in dysbindin-1 knockout mice and postmortem brain tissues from human schizophrenia patients. Furthermore, activity-dependent maturation of SREBP1 as well as ARC expression were attenuated in the dysbindin-1 knockout mice, and these deficits were restored by the atypical antipsychotic drug, clozapine. Together, results indicate an important role of dysbindin-1 in neuronal activity induced SREBP1 and ARC, which could be related to cognitive deficits in schizophrenia. |
| Databáze: | OpenAIRE |
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