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: 8420520
• 负责人: ALESSANDRO GUIDOTTI
• 金额: $ 37.68万
• 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/8420520
• 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(申请人提供)：单胺类拮抗剂药物(典型或非典型抗精神病药物)治疗精神分裂症(SZ)患者有抗精神病作用，但阴性症状和认知没有明显改善。因此，迫切需要寻找新的分子靶点来开发有效治疗认知缺陷和阴性症状的药物。在这方面，尼古丁受体激动剂是目前正在研究的一些最有希望的治疗选择(Freedman等人，2008年)。对SZ患者大脑的尸检显示：a)端脑GABA能神经元中高亲和力和低亲和力尼古丁乙酰胆碱受体(NAChR)亚型减少，这可能可被尼古丁滥用缓解；b)皮质、海马和纹状体GABA能神经元的神经病理，包括GAD67，合成GABA的谷氨酸脱羧酶的67 kDa亚型的表达降低，以及其他GABA能蛋白的表达降低，包括reelin和NMDA受体的NR2A亚单位(Guidotti等人，2005；Lewis等人，2005；Lisman等人，2008；Woo et al，2004；2008)。有证据表明，SZ脑的GABA能神经病理伴随着GABA能神经元中DNA甲基转移酶1和3a(DNMT1和DNMT3a)的过度表达(Costa等人，2007；Ruzicka等人，2007；Veldic等人，2005；2007；朱比等人，2009)。DNMT是催化几种基因启动子的CpG二核苷酸5‘位胞嘧啶碳原子甲基化的酶。为了在老鼠身上建立这种神经病理模型，我们将使用怀孕期间受到约束压力的母亲的后代。这些小鼠的特点是DNMT1和3a水平增加，GAD67水平下降。我们在正常小鼠上的初步实验(Satta等人，2008年)表明，尼古丁作用于GABA能神经元中存在的中心nAChRs(1422，17)，降低DNMT1的表达，并诱导GAD67启动子去甲基化，从而上调GAD67的表达。因此，使用合成的nAChR配体选择性地下调GABA能神经元中的DNMT可能是一种创新的尝试，目的是控制GAD67和其他基因的下调，同时保持不表达nAChRs的细胞中DNMT的功能不变。有待研究的是，选择性1422nAChR激动剂(A-85380，ABT-594)、部分激动剂(AMOP-H-OH)还是17种nAChR激动剂(PN-282987)、部分激动剂(GTS-21)或正性变构调节剂(加兰他明)更适合于下调端脑GABA能神经元的DNMT和上调GAD67的表达。因此，本研究旨在研究nAChR配体在GABA能神经元表观遗传调控中的作用，以更好地了解SZ、双相情感障碍和其他具有精神或胆碱能成分的疾病的发病机制和药物治疗。