Nicotinic receptor stimulation and epigenetic regulation of GABAergic function.

烟碱受体刺激和 GABA 功能的表观遗传调控。

• 批准号: 8279175
• 负责人: ALESSANDRO GUIDOTTI
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-10 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279175
• 关键词: Acetylcholinesterase Inhibitors; Adverse effects; Affinity; Agonist; Antibodies; Antipsychotic Agents; Autopsy; Behavior; Behavioral; Bipolar Disorder; Brain; Carbon; Cardiovascular system; Cells; Chronic; Cigarette Smoker; Cognition; Cognitive; Cognitive deficits; Complex; Corpus striatum structure; CpG dinucleotide; Cytosine; D Aspartate; DNA; DNA Methyltransferase; DNA Modification Methylases; DNMT3a; Development; Disease; Dose; Down-Regulation; Environmental Risk Factor; Enzymes; Epigenetic Process; Figs - dietary; Frequencies; GTS-21; Galantamine; Gene Expression; Gene Expression Regulation; Genes; Genetic Code; Glutamate Decarboxylase; Goals; Health; Hippocampus (Brain); Hypermethylation; Interneurons; Investigation; Lasers; Left; Ligands; Measures; Mental Depression; Methylation; Modeling; Molecular Target; Monitor; Moods; Mothers; Mus; Mutant Strains Mice; N-Methyl-D-Aspartate Receptors; Neurons; Nicotine; Nicotinic Receptors; Pathogenesis; Pathology; Patients; Peripheral Blood Lymphocyte; Pharmaceutical Preparations; Pharmacological Treatment; Play; Population; Positioning Attribute; Pregnancy; Protein Isoforms; Proteins; Psychotic Disorders; Receptor Inhibition; Regulation; Research; Role; Schizophrenia; Sensory; Slice; Smoke; Social Interaction; Sodium; Stress; Symptoms; System; Testing; Tobacco smoking; Toxic effect; Up-Regulation; acetylcholine receptor agonist; addiction; aspartate receptor; base; cholinergic; chromatin immunoprecipitation; chromatin remodeling; demethylation; gamma-Aminobutyric Acid; gastrointestinal; improved; innovation; mRNA Expression; molecular pathology; mouse model; neuropathology; nicotine abuse; novel strategies; offspring; overexpression; postsynaptic; pregnant; prenatal; prenatal stress; prepulse inhibition; promoter; receptor; research study; response; restraint stress; varenicline

DESCRIPTION (provided by applicant): Treatment of schizophrenia (SZ) patients with monoaminergic antagonist drugs (typical or atypical neuroleptics) has an antipsychotic effect, but negative symptoms and cognition are not significantly improved. Hence, there is an urgent need to find new molecular targets for the development of pharmacological agents active on cognitive deficits and negative symptoms. In this regard, nicotine receptor agonists are some of the most promising treatment options currently under investigation (Freedman et al, 2008). Postmortem examination of the brain of SZ patients reveals: a) a decrease of high and low affinity nicotinic acetylcholine receptor (nAChR) subtypes in telencephalic GABAergic neurons, which is possibly alleviated by nicotine abuse, and b) a neuropathology of cortical, hippocampal and striatal GABAergic neurons that includes decreased expression of GAD67, the 67 kDa isoform of the glutamic acid decarboxylase enzyme that synthesizes GABA, and decreased expression of other GABAergic proteins including reelin and the NR2A subunit of the NMDA receptor (Guidotti et al, 2005; Lewis et al, 2005; Lisman et al, 2008; Woo et al, 2004; 2008). Evidence suggests that this GABAergic neuropathology of SZ brain is accompanied by the overexpression of DNA-methyltransferases 1 and 3a (DNMT1 and DNMT3a) in GABAergic neurons (Costa et al, 2007; Ruzicka et al, 2007; Veldic et al, 2005; 2007; Zhubi et al, 2009). DNMTs are the enzymes that catalyze the methylation of the cytosine carbon atom in position 5' of CpG dinucleotides of several gene promoters. To model this neuropathology in mice, we will use offspring of mothers subjected to restraint stress during pregnancy. These mice are characterized by increased levels of DNMT1 and 3a and decreased GAD67. Our preliminary experiments in normal mice (Satta et al, 2008) suggest that nicotine, acting at central nAChRs (1422, 17) present in GABAergic neurons, reduces the expression of DNMT1 and elicits GAD67 promoter demethylation, thereby upregulating the expression of GAD67. Hence, the use of synthetic nAChR ligands to selectively downregulate DNMT in GABAergic neurons may be an innovative attempt to control the downregulation of GAD67 and other genes operative in selected populations of telencephalic GABAergic neurons of SZ patients, while leaving the function of DNMT in cells that do not express nAChRs intact. To be investigated is whether selective 1422 nAChR agonists (A-85380, ABT-594), partial agonists (AMOP-H-OH), or 17 nAChR agonists (PN -282987), partial agonists (GTS-21) or positive allosteric modulators (galantamine) are better suited to downregulate DNMT and upregulate GAD67 expression in telencephalic GABAergic neurons. Thus, the proposed research is aimed at studying the action of nAChR ligands on the epigenetic regulation of GABAergic neurons to better understand the pathogenesis and pharmacological treatment of sensory/cognitive components of SZ, bipolar disorder and other diseases with psychiatric or cholinergic components.

描述（由申请人提供）：精神分裂症（SZ）单胺能拮抗剂药物（典型或非典型神经疗法）患者具有抗精神病药作用，但负面症状和认知并未得到显着改善。因此，迫切需要寻找新的分子靶标，以开发活跃于认知缺陷和负面症状的药理学剂。在这方面，尼古丁受体激动剂是目前正在研究的一些最有前途的治疗方案（Freedman等，2008）。 Postmortem examination of the brain of SZ patients reveals: a) a decrease of high and low affinity nicotinic acetylcholine receptor (nAChR) subtypes in telencephalic GABAergic neurons, which is possibly alleviated by nicotine abuse, and b) a neuropathology of cortical, hippocampal and striatal GABAergic neurons that includes decreased expression of GAD67, the 67合成GABA的谷氨酸脱羧酶的67 KDA同种酶，以及其他GABA能蛋白的表达降低，包括reelin和NR2A NMDA受体的NR2A亚基（Guidotti等，2005； Lewis等人，2005; Lewis等，2005; Lisman，2005; Lisman Et al，2008; 有证据表明，SZ脑的这种GABA能神经病理学伴随着DNA-甲基转移酶1和3A（DNMT1和DNMT3A）的过表达（Costa等人，Costa等，2007; Ruzicka et al，2007; veldic et al，2005; veldic et al，2007; zhubi; zhubi et al，2007; Ruzicka et al。 DNMT是催化几种基因启动子CpG二核苷酸位置5'的胞嘧啶碳原子的甲基化的酶。为了对小鼠的这种神经病理进行建模，我们将使用怀孕期间受到克制压力的母亲的后代。这些小鼠的特征是DNMT1和3A的水平升高，而GAD67降低。 我们在正常小鼠中的初步实验（Satta等，2008）表明，尼古丁在GABA能神经元中作用于中央NACHRS（1422，17），可降低DNMT1的表达，并降低GAD67启动子脱甲基的表达，从而降低GAD67的表达。因此，使用合成NACHR配体在GABA能神经元中有选择地下调DNMT可能是一种创新的尝试，以控制GAD67和其他基因在SZ患者的选定脑脑脑脑群中的下调和其他基因的作用，而SZ患者的SZ患者则不愿意表达DNMT的功能，并不能表达nACHRS NACHRS的功能。 To be investigated is whether selective 1422 nAChR agonists (A-85380, ABT-594), partial agonists (AMOP-H-OH), or 17 nAChR agonists (PN -282987), partial agonists (GTS-21) or positive allosteric modulators (galantamine) are better suited to downregulate DNMT and upregulate GAD67 expression in脑脑脑GABA能神经元。因此，拟议的研究旨在研究NACHR配体对GABA能神经元的表观遗传调节的作用，以更好地了解SZ的感觉/认知成分的发病机理和药理学治疗，双相情感障碍和其他疾病与精神病或胆碱能力成分。