GABAergic and Reelin Deficits in Schizophrenia

精神分裂症中的 GABA 能和 Reelin 缺陷

• 批准号: 8264216
• 负责人: seyyed HOSSEIN FATEMI
• 金额: $ 33.64万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264216
• 关键词: Affect; Age; Anterior; Area; Autopsy; Biochemical; Biological Markers; Bipolar Disorder; Brain; Brain region; Cerebellum; Cognition; Delusions; Depressed mood; Development; Disease; Down-Regulation; Emotions; Family; Functional disorder; GABA Receptor; Gene Expression; Gene Expression Profiling; Gene Family; Genes; Glutamate Decarboxylase; Hallucinations; Hippocampus (Brain); In Situ Hybridization; Lateral; Major Depressive Disorder; Measures; Messenger RNA; MicroRNAs; Neurodevelopmental Disorder; Outcome; Pathology; Phosphotransferases; Prevalence; Proteins; Proto-Oncogene Proteins c-akt; Sampling; Schizophrenia; Signal Pathway; Signal Transduction; Signaling Molecule; Social Functioning; Structure; Symptoms; System; Techniques; Testing; Western Blotting; apolipoprotein E receptor 2; base; frontal lobe; gamma-Aminobutyric Acid; immunocytochemistry; member; public health relevance; receptor; reelin protein; sex; src-Family Kinases; tau Proteins; young adult

DESCRIPTION (provided by applicant): Schizophrenia is a neurodevelopmental disorder that affects young adults and is manifested by a disruption in cognition and emotion, along with negative (i.e., apathy, poor or nonexistent social functioning) and positive (presence of hallucinations, delusions) symptoms, and a lifetime prevalence of 1%. Our proposal will evaluate the degree of involvement of GABAergic receptor families, Reelin, and GAD65 and GAD67 kDa and their constituent signaling systems in postmortem brain samples of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and matched controls. The central hypothesis of this application is that expression of molecules involved in the Reelin and GABAergic signaling pathways are altered in subjects with schizophrenia, bipolar disorder, and major depression resulting in dysfunctional signaling and consequent brain abnormalities in these disorders. We plan to test our central hypothesis and accomplish the objectives of this application by pursuing the following three Specific Aims: 1) Systematically determine mRNA and protein levels for members of the Reelin signaling system in frontal cortex, anterior hippocampus, and lateral cerebellum of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and matched controls; 2) Determine the mRNA and protein levels of GAD65, GAD67, and selected GABA receptors in frontal cortex, anterior hippocampus, and lateral cerebellum of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and matched controls; and 3) Characterize microRNA and miRNA target gene expression in frontal cortex, hippocampus, and cerebellum of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and controls. We will employ previously established qRT-PCR, western blotting, immunocytochemistry, in situ hybridization and miRNA microarray techniques to quantify various mRNA and protein species. This proposal has the potential to accomplish multiple objectives: 1) Discover systematic changes in Reelin, its receptors, and downstream molecules, in key abnormal structures in schizophrenia, bipolar disorder and major depression: frontal cortex (Brodman's area (BA) 6), anterior hippocampus, and lateral cerebellum; 2) Determine coordinated changes in molecules and identifying relationships among molecules of the Reelin signaling system; 3) Characterize changes in the mRNA and protein levels for GABA receptors, GAD65 and GAD67 kDa molecules in anterior hippocampal, lateral cerebellar, and frontal cortices of subjects with schizophrenia vs. matched bipolar, depressed, and healthy controls; 4) Discover relationships among Reelin and GABAergic signaling system molecules that explain dysfunction of these two systems in the pathology of schizophrenia, bipolar disorder, and major depression; and 5) Test whether miRNAs may be responsible for altered expression of Reelin and GABAergic signaling molecules in subjects with schizophrenia, bipolar disorder, and major depression. PUBLIC HEALTH RELEVANCE: Schizophrenia is a neurodevelopmental disorder that affects young adults and is manifested by a disruption in cognition and emotion, along with negative (i.e., apathy, poor or nonexistent social functioning) and positive (presence of hallucinations, delusions) symptoms. There is a lifetime prevalence of 1%. Our proposal will evaluate the degree of involvement of GABAergic receptor families, Reelin, and GAD65 and GAD67 kDa and their constituent signaling systems in postmortem brain samples of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and matched controls. Such outcomes will be significant, because they are expected to identify biochemical mechanisms responsible for abnormal brain development.

描述（由申请人提供）：精神分裂症是一种影响年轻人的神经发育障碍，表现为认知和情绪紊乱，以及消极（即冷漠、社会功能差或不存在）和积极（出现幻觉、妄想）症状，终生患病率为 1%。我们的提案将评估 GABA 受体家族、Reelin、GAD65 和 GAD67 kDa 及其组成信号系统在精神分裂症受试者与双相情感障碍、重度抑郁症受试者和匹配对照受试者死后大脑样本中的参与程度。该申请的中心假设是，在患有精神分裂症、双相情感障碍和重度抑郁症的受试者中，参与 Reelin 和 GABAergic 信号传导途径的分子表达发生改变，导致这些疾病中的信号传导功能障碍和随之而来的大脑异常。我们计划通过追求以下三个具体目标来测试我们的中心假设并实现本申请的目标：1）系统地确定精神分裂症受试者与双相情感障碍、重性抑郁症受试者和匹配对照受试者的额叶皮层、海马前部和小脑外侧中 Reelin 信号系统成员的 mRNA 和蛋白质水平； 2) 确定精神分裂症受试者与双相情感障碍、重度抑郁症受试者和匹配对照受试者额叶皮层、前海马和小脑外侧中 GAD65、GAD67 和选定 GABA 受体的 mRNA 和蛋白水平； 3) 表征精神分裂症受试者与双相情感障碍、重度抑郁症受试者和对照受试者额叶皮层、海马体和小脑中 microRNA 和 miRNA 靶基因表达的特征。我们将采用先前建立的 qRT-PCR、蛋白质印迹、免疫细胞化学、原位杂交和 miRNA 微阵列技术来量化各种 mRNA 和蛋白质种类。该提案有可能实现多个目标：1）发现Reelin及其受体和下游分子在精神分裂症、双相情感障碍和重度抑郁症的关键异常结构中的系统变化：额叶皮层（布罗德曼区（BA）6）、海马前部和小脑外侧； 2) 确定分子的协调变化并识别Reelin信号系统分子之间的关系； 3) 表征精神分裂症受试者与相匹配的双相情感障碍、抑郁症和健康对照者海马前部、小脑外侧和额叶皮质中 GABA 受体、GAD65 和 GAD67 kDa 分子的 mRNA 和蛋白质水平的变化； 4) 发现Reelin和GABAergic信号系统分子之间的关系，解释这两个系统在精神分裂症、双相情感障碍和重度抑郁症病理学中的功能障碍； 5) 测试 miRNA 是否可能导致精神分裂症、双相情感障碍和重度抑郁症受试者中 Reelin 和 GABAergic 信号分子表达的改变。 公共卫生相关性：精神分裂症是一种影响年轻人的神经发育障碍，表现为认知和情绪紊乱，以及消极（即冷漠、社会功能差或不存在）和积极（出现幻觉、妄想）症状。终生患病率为 1%。我们的提案将评估 GABA 受体家族、Reelin、GAD65 和 GAD67 kDa 及其组成信号系统在精神分裂症受试者与双相情感障碍、重度抑郁症受试者和匹配对照受试者死后大脑样本中的参与程度。这样的结果将是意义重大的，因为它们有望确定导致大脑发育异常的生化机制。