GABAergic molecular pathology in schizophrenia

精神分裂症的 GABA 分子病理学

• 批准号: 7365158
• 负责人: ERMINIO COSTA
• 金额: $ 29.39万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-21 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7365158
• 关键词: 7q22; Address; Adult; Affect; Animals; Anticonvulsants; Antipsychotic Agents; Apical; Area; Autopsy; Behavioral; Bipolar Disorder; Brain; Catecholamines; Characteristics; Chromatin; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 7; Clinical; Code; Complex; Consensus; Corpus striatum structure; Count; CpG Islands; Cytosine; DNA; DNA Methyltransferase; DNA Modification Methylases; Data; Defect; Dendrites; Dendritic Spines; Detection; Disease; Disease Progression; Dose; Down-Regulation; Drug Delivery Systems; Enzymes; Epigenetic Process; Event; Extracellular Matrix; Fire - disasters; Functional disorder; Gene Expression; Gene Mutation; Genes; Genetic Polymorphism; Genetic Transcription; Genomics; Glutamate Decarboxylase; Glutamic Acid; Heritability; Heterochromatin; Hippocampus (Brain); Histone Acetylation; Histone Deacetylase Inhibitor; Histone Deacetylation; Histones; Human; Hypermethylation; In Vitro; Individual; Inherited; Injection of therapeutic agent; Integrins; Interneurons; Intervention; Island; Learning; Lysine; Major Depressive Disorder; Mediating; Memory; Messenger RNA; Methionine; Methylation; Mood stabilizers; Morbidity - disease rate; Mus; Neurodevelopmental Disorder; Neurons; Neuropil; Numbers; Occipital lobe; Pathology; Patients; Perinatal; Pharmaceutical Preparations; Play; Population; Predisposition; Prefrontal Cortex; Principal Investigator; Process; Promoter Regions; Protein Biosynthesis; Proteins; Regulation; Research Personnel; Risk Factors; Risperidone; Role; Schizophrenia; Site; Social Interaction; Symptoms; Synaptic Cleft; System; Tail; Temporal Lobe; Testing; Transcript; Transferase; Translations; Up-Regulation; Vertebral column; Week; Work; caudate nucleus; chromatin remodeling; day; demethylation; density; frontal lobe; gamma-Aminobutyric Acid; gene function; genetic regulatory protein; hippocampal pyramidal neuron; histone acetyltransferase; histone methyltransferase; inhibitor/antagonist; mRNA Expression; molecular pathology; neurochemistry; neurodevelopment; neuropathology; neuropsychiatry; postsynaptic; prenatal; prepulse inhibition; programs; promoter; protein expression; receptor; transcription factor; valproate; volunteer

DESCRIPTION (provided by applicant): Prefrontal cortex (RFC) GABAergic interneurons are a major target for the molecular pathology associated with schizophrenia (SZ) morbidity; their alteration may contribute to the reduction of cortical neuropil, which is an important component of SZ pathophysiology. Cortical GABAergic neurons participate in the orchestration of cortical pyramidal neuron population firing via the release of GABA on GABAA and GABAB receptors and modulate dendritic spine plasticity via the translation of spine resident mRNAs facilitated by the GABAergic neuron release of reelin acting on integrin receptors located on dendritic spine postsynaptic densities. In SZ cortical GABAergic neurons, the synthesis of GABA and reelin is reduced because of a downregulation in GAQ67 and reelin mRNA expressions. Very probably this is due to an increased expression in GABAergic neurons of DNA-(cytosine 5)-methyltransferase1 (DNMT1) that contributes to the epigenetic hypermethylation of CpG islands and promoters expressed in reelin and GAD67 genes and to the consequent decreased synthesis of these two gene transcripts. Thus, we hypothesize that downregulation of GABAergic function due to an epigenetic mechanism may be an important primary process operative in SZ morbidity. We will study whether: 1) in addition to BA9 and BA10 GABAergic neurons, DNMT1 is coexpressed with reelin and GAD67, in the GABAergic neurons of the occipital cortex and caudate nucleus; 2) in every GABAergic neuron, the increase of DNMT1 expression coincides with a decrease of reelin and GAD67 expression; 3) the increase of DNMT1 and the decrease of reelin and GAD67 expression also extend to brains of bipolar disorder patients; 4) DNMT1 establishes a partnership with complexes including histone deacetylases and histone methylases, two prominent enzymes to regulate the code whereby histones control accessibility of transcription factors or DNMT1 to targeted regulatory sites in gene promoters. A better understanding of how epigenetic mechanisms can regulate reelin and GAD67 gene transcription may allow the discovery of new drug targets that can reprogram transcription and perhaps modify pathologies related to epigenetically-induced downregulation of gene expression in SZ.

描述（由申请人提供）：前额皮质（RFC）GABA能中间神经元是与精神分裂症（SZ）发病相关的分子病理学的主要目标；它们的改变可能导致皮质神经纤维的减少，而皮质神经纤维是 SZ 病理生理学的重要组成部分。皮质 GABA 能神经元通过在 GABAA 和 GABAB 受体上释放 GABA 来参与皮质锥体神经元群放电的编排，并通过作用于位于树突棘突触后密度上的整合素受体的 GABA 能神经元释放 r​​eelin 促进树突棘驻留 mRNA 的翻译来调节树突棘可塑性。在 SZ 皮质 GABA 能神经元中，由于 GAQ67 和 reelin mRNA 表达下调，GABA 和 reelin 的合成减少。这很可能是由于 DNA-(胞嘧啶 5)-甲基转移酶 1 (DNMT1) 的 GABA 能神经元表达增加，导致 reelin 和 GAD67 基因中表达的 CpG 岛和启动子的表观遗传高甲基化，并导致这两个基因转录物的合成减少。因此，我们假设表观遗传机制导致的 GABA 能功能下调可能是 SZ 发病的一个重要的主要过程。我们将研究：1）除了BA9和BA10 GABA能神经元之外，DNMT1是否与reelin和GAD67在枕叶皮层和尾状核的GABA能神经元中共表达； 2）在每个GABA能神经元中，DNMT1表达的增加与reelin和GAD67表达的减少相一致； 3）双相情感障碍患者大脑中DNMT1的增加以及reelin和GAD67表达的减少也延伸到大脑； 4) DNMT1 与包括组蛋白脱乙酰酶和组蛋白甲基化酶在内的复合物建立伙伴关系，这两种重要的酶用于调节组蛋白控制转录因子或 DNMT1 对基因启动子中目标调节位点的可及性的代码。更好地了解表观遗传机制如何调节 reelin 和 GAD67 基因转录可能有助于发现新的药物靶点，这些靶点可以重新编程转录，并可能改变与表观遗传诱导的 SZ 基因表达下调相关的病理学。