Pyramidal neuron hypoactivity in schizophrenia cortex

精神分裂症皮质锥体神经元活性低下

• 批准号: 10452726
• 负责人: Kirsten Schoonover
• 金额: $ 8.78万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452726
• 关键词: ATP phosphohydrolase; Address; Affect; Alleles; Animals; Antibodies; Antipsychotic Agents; Autopsy; Behavior; Behavioral; Binding Proteins; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; CREB1 gene; Candidate Disease Gene; Carrier Proteins; Cell Culture Techniques; Cognitive deficits; Collection; Conflict (Psychology); Copper; Data; Data Collection; Delusions; Demyelinations; Disease; Dopamine; Dopamine-beta-monooxygenase; Drug Targeting; Educational process of instructing; Electron Microscopy; Epigenetic Process; Exhibits; Family; Fiber; Foundations; Future; Genes; Genetic; Genotype; Goals; Hallucinations; Hippocampus (Brain); Homeostasis; Hypermethylation; Immunohistochemistry; Impaired cognition; Impairment; Individual; Knock-out; Knockout Mice; Knowledge; Learning; Learning Skill; Link; MAP Kinase Gene; Mediating; Mediation; Mental disorders; Mentors; Messenger RNA; Metabolism; Methylation; Midbrain structure; Mitochondria; Molecular; Mus; Neuraxis; Pathology; Pathway interactions; Patients; Peripheral; Persons; Population; Protein Deficiency; Protein Isoforms; Proteins; Regulation; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Schizophrenia; Starvation; Substantia nigra structure; Symptoms; System; Techniques; Testing; Tissues; Variant; Western Blotting; Wild Type Mouse; Writing; behavioral impairment; brain volume; cognitive function; drug development; dystrobrevin; emerging adult; experimental study; gene therapy; genetic variant; high risk; hippocampal pyramidal neuron; hypocupremia; interest; learning progression; meetings; monoamine; mouse model; multidisciplinary; myelination; new therapeutic target; novel marker; preadolescence; promoter; protein expression; quetiapine; risk variant; skills; stem; white matter

Schizopphrenia (SZ) affects 1% of the world population. Allelic variants of the dystrobrevin binding protein 1 (DTNBP1) gene, now a top SZ candidate gene, are associated with fiber tract impairments in healthy people and reduced brain volume in preteens- both SZ symptoms. However, the downstream effects of decreased dysbindin are poorly understood. Dysfunctional dysbindin decreases the copper-transporting P-type ATPase (ATP7A) and the copper transporter CTR1. ATP7A and CTR1 facilitate copper transport between the blood and the brain. The role of copper in SZ has been controversial, with many studies finding increased blood copper in patients. However, these studies have not considered copper may build up in the blood because it cannot get into the brain. Copper-decreasing experimental manipulations produce demyelination, dopamine increases, and SZ-like behavioral impairments. Taken together, dysbindin/copper alterations can result in SZ- like pathology such as impaired white matter integrity, excess dopamine, and altered mitochondrial activity, and yet this combined pathway remains largely unstudied. Overall, I hypothesize copper transport alterations contribute to SZ pathology, potentially through decreased dysbindin expression. I will test this in postmortem SZ brain, first-episode antipsychotic-naïve SZ patients, and a dysbindin knockout mouse model. Specific Aim 1: I have learned western blotting, and am now learning immunohistochemical analysis. Specific Aim 2A. We will test the copper state of postmortem substantia nigra and hippocampus, and the relationship of this state to copper transporters ATP7A/CTR1 in both treated and untreated SZ. Furthermore, we will assess the mechanism of action of antipsychotics in relation to these variables. Specific Aim 2B. To discover potential schizophrenia biomarkers, we will assess peripheral copper state and its relationship to copper transporters and methylation status of DTNBP1, SLC31A1(CTR1), and ATP7A before and after 6 weeks of antipsychotic treatment in first-episode, antipsychotic-naïve SZ patients. Specific Aim 2C. In dysbindin knockout, heterozygous, and wild-type mice, we will test peripheral, hippocampal, and nigral copper state, and the relation to copper transporters ATP7A/CTR1, cognitive deficits, and the mechanism of antipsychotic mediated changes before and after 28 days quetiapine treatment. Specific Aim 3: These studies will provide the first evidence of SZ brain copper state, and resolve the juxtaposition between excess copper in SZ blood and the SZ-like symptoms induced by copper deficit. Furthermore, these studies will provide new data about risk gene dysbindin and its effects on copper transporters (a previously unstudied pathway in SZ) and a potential mechanism of antipsychotic rescue of copper starvation deficits, which could yield novel targets for drug development. I will learn quantitative RT- PCR, methylation assay, immunohistochemistry, electron microscopy and tissue sectioning, brain collection, scientific writing, lab and animal management, and all that these skills entail, as well as proficient teaching.

精神分裂症（SZ）影响着世界上1%的人口。肌营养不良蛋白结合蛋白的等位变异