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Genetic Mouse Models for the Study of Serotonin, Dopamine and Glutamate Function and Behavior

用于研究血清素、多巴胺和谷氨酸功能和行为的基因小鼠模型

基本信息

批准号：
8939930
负责人：
DENNIS L MURPHY
金额：
$ 9.32万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8939930
关键词：
5-Hydroxytryptophan Adverse effects Affect Annual Reports Anti-Anxiety Agents Antidepressive Agents Antipsychotic Agents Asians Attention deficit hyperactivity disorder Behavior Behavioral Binding Sites Brain Caucasians Caucasoid Race Clozapine Collaborations Data Development Disease Dopamine Drug usage EAAT3 Emotional Extracellular Fluid Gene Mutation Genes Genetic Genetic Models Genetic Polymorphism Genetic Predisposition to Disease Genotype Gilles de la Tourette syndrome Glutamate Transporter Glutamates Health Homeostasis Human Individual Interneurons Investigation Journals Knock-out Knockout Mice Knowledge Laboratories Lead Life Light Mediating Mental disorders Metabolic Modeling Molecular Monoamine Oxidase Mus National Institute on Alcohol Abuse and Alcoholism Nature Neurodevelopmental Disorder Neurons Neurosciences Neurotransmitters Obsessive-Compulsive Disorder Paper Patients Peer Review Personality Phenotype Physiological Population Promoter Regions Protocols documentation PubMed Publications Publishing Reaction Reporting Research Role Selective Serotonin Reuptake Inhibitor Serotonin Serotonin Agents Serotonin Syndrome Societies Stereotyped Behavior Synapses Syndrome System Temperature Time Toxic effect Transgenic Mice Transgenic Organisms Tranylcypromine Treatment Efficacy Variant Work abstracting dopamine transporter gene environment interaction genetic variant high risk human data human disease meetings mouse model neurochemistry neuropsychiatry overexpression rare variant receptor response serotonin transporter tool trait

项目摘要

As recently reviewed by us, SERT-deficient +/- and -/- mice have gene-proportionate increases in extracellular fluid serotonin concentrations, i.e., 5- or 7-fold excesses respectively over wildtype +/+ mice. At the same time, SERT -/- mice have a marked deficit of intracellular, releasable serotonin. To investigate a rare variant in the serotonin transporter, I425V, strongly associated with obsessive-compulsive disorder and more recently, Tourettes Disorder in our own studies published over the last several years and most recently last year, a mouse model was created in C57B6 mice with this gene alteration. Preliminary results of initial investigations were reported at the ACNP meeting in 2013 (Ramamoorthy, Murphy DL, et al.) and will also be reported at the Society for Neuroscience meeting on November, 2014 Continuing advances have been made in our studies of serotonin-related toxic reactions, including the serotonin syndrome. Most commonly, this toxicity occurs as a side effect in humans treated with certain antidepressant and anti-anxiety drugs. Importantly, its milder forms contribute to reduced therapeutic efficacy or a requirement to interrupt treatment in some individuals treated with SRIs. Our earlier studies exploring this behavioral and temperature-related syndrome in SERT-deficient mice revealed a genetic vulnerability to a markedly exaggerated serotonin syndrome when these mice were exposed to the metabolic precursor of serotonin, 5-HTP, or to other serotonergic drugs such as the monoamine oxidase-inhibiting (MAO-I) antidepressant, tranylcypromine. In addition to the serotonin syndrome behavioral changes, exaggerated alterations in temperature responses were also found in SERT- and MAO-deficient mice. We have further extended these studies to include dopamine transporter (DAT) knockout mice to further explicate the unusual behavioral feature, some resembling compulsive, stereotyped behaviors related to human obsessive-compulsive disorder (OCD). We have also created both conditional EAAT3 over-expressing and conditional EAAT3 knockout mice, to investigate the functional consequences of altered expression of this important glutamate transporter. We are currently characterizing these mice at molecular, neurochemical and behavioral levels. In addition, A report about these mice was published in abstract form this year (Moya PR et al., 2013).In collaboration with Dr. Andrew Holmes at NIAAA we plan to characterize behavioral phenotypes that might arise from GAD65-Cre-mediated EAAT3 overexpression in interneurons that might shed light into the role of EAAT3 in neuropsychiatric disorders such as OCD. These findings in these mouse genetic models suggest the likelihood that humans with lower-expressing SLC6A4 SS, SLg and LgLg genotypes, or other SERT variants as well as SLC6A3 and SLC1A1 variants that may lead to 50-100% alterations in binding sites or transport function, may be at higher risk to develop neurodevelopmental disorders. Of special note, it is likely that relatively mild serotonin syndrome occurrence may contribute to early discontinuation of SRIs and other side effects during SRI treatment of neuropsychiatric patients that are strongly associated with the lower-expressing SLC6A4. Likewise variants in SLC6A3 and SLC1A1 genes have recently been found to be associated with multiple neuropsychiatric disorders such as ADHD and OCD. Our Laboratory has contributed to research on variants in these genes as noted in our other 2014 Annual Report ZIA MH000332-36 LCS. Given this transgenic mouse data and human SLC6A4, SLC6A3 and SLC1A1 polymorphism data, we have joined in multiple collaborative gene-hunting efforts to find and examine functional likely involved in neuropsychiatric disorders. Overall, the data accumulated by our Lab, as referenced below and previously in over 800 Pubmed references, support the use of different genetically modified mice as vulnerability models for humans with SERT, DAT, EAAT3 and other gene variants with regard to gene-gene and gene-environment interactions that contribute to human diseases and the pharmacologic treatment of multiple psychiatric disorders. We have published reviews of our work on these murine models in major journals (e.g., Murphy and Lesch, Nature Neuroscience, 2008). Citation numbers of other papers that have referenced our scientific reports number over 3500 as of August, 2014. The protocol number for this report is LCS 04.

正如我们最近所评论的，SERT 缺陷的 +/- 和 -/- 小鼠的细胞外液血清素浓度与基因成比例增加，即分别比野生型 +/- 小鼠高 5 倍或 7 倍。同时，SERT -/- 小鼠细胞内可释放的血清素明显缺乏。为了研究血清素转运蛋白 I425V 中的一种罕见变异（该变异与强迫症以及最近的抽动秽语症密切相关），我们在过去几年和最近去年发表的研究中，在具有这种基因改变的 C57B6 小鼠中创建了小鼠模型。初步调查的初步结果已在 2013 年的 ACNP 会议上报告（Ramamoorthy、Murphy DL 等人），也将在 2014 年 11 月的神经科学学会会议上报告我们对血清素相关毒性反应（包括血清素综合征）的研究不断取得进展。最常见的是，这种毒性是用某些抗抑郁药和抗焦虑药治疗的人类的副作用。重要的是，其较温和的形式会降低某些接受 SRI 治疗的患者的治疗效果或需要中断治疗。我们早期的研究探索了 SERT 缺陷小鼠的这种行为和温度相关综合征，揭示了当这些小鼠暴露于血清素的代谢前体 5-HTP 或其他血清素能药物（如单胺氧化酶抑制 (MAO-I) 抗抑郁药反苯环丙胺）时，这些小鼠对明显夸大的血清素综合征具有遗传脆弱性。除了血清素综合征行为变化外，SERT 和 MAO 缺陷小鼠的温度反应也发生了过度变化。我们进一步扩展了这些研究，将多巴胺转运蛋白（DAT）敲除小鼠纳入其中，以进一步解释这种不寻常的行为特征，其中一些类似于与人类强迫症（OCD）相关的强迫性刻板行为。我们还创建了条件性 EAAT3 过表达和条件性 EAAT3 敲除小鼠，以研究这种重要的谷氨酸转运蛋白表达改变的功能后果。我们目前正在分子、神经化学和行为水平上表征这些小鼠。此外，今年以摘要形式发表了一份关于这些小鼠的报告（Moya PR et al., 2013）。与 NIAAA 的 Andrew Holmes 博士合作，我们计划表征中间神经元中 GAD65-Cre 介导的 EAAT3 过度表达可能产生的行为表型，这可能有助于揭示 EAAT3 在神经精神疾病（如强迫症）中的作用。这些小鼠遗传模型中的这些发现表明，具有较低表达的 SLC6A4 SS、SLg 和 LgLg 基因型或其他 SERT 变体以及可能导致结合位点或转运功能发生 50-100% 改变的 SLC6A3 和 SLC1A1 变体的人类，患神经发育障碍的风险可能更高。特别值得注意的是，相对轻微的血清素综合征的发生可能会导致神经精神病患者在 SRI 治疗期间提前停止 SRI 和其他副作用，这些副作用与低表达的 SLC6A4 密切相关。同样，最近发现 SLC6A3 和 SLC1A1 基因的变异与多种神经精神疾病（例如 ADHD 和 OCD）有关。正如我们的另一份 2014 年年度报告 ZIA MH000332-36 LCS 中所述，我们的实验室对这些基因变异的研究做出了贡献。鉴于转基因小鼠数据和人类 SLC6A4、SLC6A3 和 SLC1A1 多态性数据，我们加入了多项合作基因搜寻工作，以寻找和检查可能与神经精神疾病有关的功能。总体而言，我们实验室积累的数据（如下文和之前在 800 多篇 Pubmed 参考文献中引用的）支持使用不同的转基因小鼠作为具有 SERT、DAT、EAAT3 和其他基因变异的人类易感性模型，这些变异涉及导致人类疾病和多种精神疾病的药物治疗的基因-基因和基因-环境相互作用。我们已在主要期刊上发表了对这些小鼠模型的研究评论（例如 Murphy 和 Lesch，Nature Neuroscience，2008）。截至 2014 年 8 月，引用我们科学报告的其他论文的引用数量已超过 3500 篇。该报告的协议号是 LCS 04。