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.

正如我们最近综述的那样，缺乏SERT缺陷+/-和 - / - 小鼠具有基因 - 比例的增加的细胞外流体5-羟色胺浓度，即比野生型 +/ +小鼠分别超过5或7倍。同时，SERT - / - 小鼠具有明显的细胞内，可释放的5-羟色胺。为了调查5-羟色胺转运蛋白中的罕见变体I425V，与强迫症的强烈相关，最近，我们自己的研究中发表的Tourettes Disery在过去几年中发表了，最近去年，C57B6小鼠在C57B6小鼠中创建了一种基因改变的小鼠模型。在2013年的ACNP会议上报告了初步调查的初步结果（Ramamoorthy，Murphy DL等），也将在2014年11月的神经科学会议上报告在我们对5-羟色胺综合征在内的5-羟色胺相关毒性反应的研究中，已经取得了持续的进步。最常见的是，这种毒性是通过某些抗抑郁药和抗焦虑药治疗的人类的副作用。重要的是，它的温和形式有助于降低治疗功效或中断用SRI治疗的个体中断治疗的要求。我们的早期研究探索了缺乏Sert的小鼠这种行为和温度相关综合征，当这些小鼠暴露于5-htp的代谢前体时，遗传脆弱性明显夸大了5-羟色胺综合征。除了血清素综合征的行为变化外，在SERT和MAO缺陷型小鼠中还发现了温度反应的夸张变化。我们进一步扩展了这些研究，以包括多巴胺转运蛋白（DAT）基因敲除小鼠，以进一步阐明异常的行为特征，某些类似于强迫性的，与人类强迫症相关的强迫性，定型行为（OCD）。我们还创建了有条件的EAAT3过表达和有条件的EAAT3基因敲除小鼠，以研究这种重要的谷氨酸转运蛋白的表达改变的功能后果。我们目前正在表征这些小鼠在分子，神经化学和行为水平上。 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. 这些小鼠遗传模型中的这些发现表明，具有较低表达SLC6A4 SS，SLG和LGLG基因型或其他SERT变体以及SLC6A3和SLC1A1变体的人类可能会导致粘合部位或运输功能中的50-100％变化，可能会导致较高的风险，从而导致Neurorders的风险更高。特别值得注意的是，在SRI治疗神经精神病患者期间，相对温和的5-羟色胺综合征的发生可能会导致SRIS和其他副作用的早期终止，这些患者与较低表达的SLC6A4密切相关。同样，最近发现SLC6A3和SLC1A1基因中的变体与多种神经精神疾病（如ADHD和OCD）有关。如我们的其他2014年年度报告ZIA MH000332-36 LCS所述，我们的实验室对这些基因的变体进行了研究。鉴于这种转基因小鼠数据和人类SLC6A4，SLC6A3和SLC1A1多态性数据，我们已经加入了多种协作基因追求工作，以查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，如下所述，以前在800多个PubMed参考文献中，支持使用不同的遗传修饰的小鼠作为sert，dat，eaat3和其他基因变异的人类脆弱性模型，这些变体在基因 - 基因和基因 - 环境相互作用方面有助于对人类疾病和多种心理疾病的疾病治疗。我们已经在主要期刊上发表了有关这些鼠模型的工作的评论（例如Murphy和Lesch，Nature Neuroscience，2008年）。截至2014年8月，引用了我们的科学报告数量超过3500的其他论文的引文数量。该报告的协议编号为LCS 04。