Metabotropic Glutamate Receptor Regulation in MeCP2-Related Disorders

MeCP2 相关疾病中代谢型谷氨酸受体的调节

• 批准号: 8898219
• 负责人: COLLEEN M NISWENDER
• 金额: $ 23.54万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898219
• 关键词: Adult; Adverse effects; Affect; Affinity; Animals; Area; Attention deficit hyperactivity disorder; Autistic Disorder; Behavioral; Binding; Binding Sites; Brain; Breathing; Characteristics; Chemosensitization; Child; Chronic; Cognitive deficits; Coupled; CpG Islands; DNA; Data; Defect; Development; Disease; Emergency Situation; Excitatory Postsynaptic Potentials; Exhibits; G-Protein-Coupled Receptors; Gene Expression Regulation; Genes; Genetic Polymorphism; Genetic Transcription; Glutamates; Health; Hippocampus (Brain); Human; Impairment; In Vitro; Intervention; Knock-in Mouse; Knock-out; Knockout Mice; Language; Learning; Link; Long-Term Potentiation; Mediating; Memory; Mental Depression; Messenger RNA; Metabotropic Glutamate Receptors; Methyl-CpG-Binding Protein 2; Modeling; Motor; Mus; Mutant Strains Mice; Mutation; Neuronal Dysfunction; Neurons; Pattern; Phenotype; Physiologic pulse; Presynaptic Terminals; Proteins; Regulation; Repression; Rett Syndrome; Risk; Rodent; Role; Schizophrenia; Seizures; Slice; Staging; Stereotyped Behavior; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Syndrome; Testing; Therapeutic; conditioned fear; dosage; drug development; gamma-Aminobutyric Acid; improved; in vivo; knockout animal; mature animal; metabotropic glutamate receptor 7; mouse model; mutant; nervous system disorder; neurotransmission; novel; overexpression; presynaptic; prevent; promoter; receptor; skills; therapeutic target; tool; transcription factor

DESCRIPTION (provided by applicant): Rett syndrome is a devastating neurological disorder characterized by autism, language skill loss, stereotyped behaviors, motor delays, cognitive deficits, seizures, and breathing abnormalities. Most cases result from mutations in or loss of the protein MeCP2, a transcription factor that binds to methylated CpG regions of DNA. Knockout of MeCP2 in mice recapitulates many Rett phenotypes and re-expression of MeCP2 in adult mouse neurons corrects phenotypic deficits, suggesting that treatments given after disease development may be therapeutically viable. However, children with MeCP2 Duplication syndrome also exhibit significant Rett-like symptoms, indicating that a precise level of MeCP2 is critical for maintaining normal neuronal function. We have found that the gene encoding metabotropic glutamate receptor 7 (GRM7/mGlu7), a receptor which modulates glutamate and GABA release, is positively regulated by MeCP2 both in vitro and in an in vivo Mecp2 knockout mouse model. Importantly, we have found that mGlu7 mRNA and protein levels are significantly decreased in multiple brain areas in Mecp2 KO mice. These results suggest that the GRM7 gene appears to be true and novel target of MeCP2. If correct, we predict that mGlu7 levels will be elevated in mice overexpressing MeCP2, which represent a model for MeCP2 Duplication syndrome. As one function of mGlu7 activation is to decrease glutamate release from presynaptic terminals, we hypothesized that aberrantly decreased levels of mGlu7 in Mecp2 KO mice enhances glutamatergic tone. It has been demonstrated in Mecp2 KO, knock-in, and overexpressing mice that synaptic transmission, as well as long term potentiation, at Schaffer Collateral-CA1 (SC-CA1) synapses is altered. Interestingly, the impairment in each case appears to be mediated, in part, by a presynaptic mechanism, with mice lacking Mecp2 exhibiting reduced paired pulse facilitation, an observation consistent with increased glutamate release from presynaptic terminals. In contrast, mice overexpressing Mecp2 show increases in paired pulse ratios, suggestive of decreased glutamate release. As mGlu7 is the predominant mGlu present at the SC-CA1 synapse in adult animals, these defects in neurotransmission, coupled with our findings that mGlu7 levels are reduced in Mecp2 KO mice, are consistent with a role for presynaptic mGlu7 as a major controller of glutamate release at SC-CA1 synapses, potentially resulting in cognitive deficits seen in these animals. We have confirmed previous results showing that synaptic plasticity and long term potentiation are altered in Mecp2-/y mice and show, importantly, that potentiation of mGlu7 activity can rescue these defects. We propose to test the hypotheses that mGlu7 levels are conversely increased in an MeCP2 Duplication mouse model, further substantiating a role for MeCP2 in mGlu7 gene regulation. Additionally, we will test the hypotheses that modulation of mGlu7 activity using pharmacological tools will normalize synaptic plasticity and behavioral deficits in mice under- and overexpressing the MeCP2 protein.

描述（由申请人提供）：Rett综合征是一种破坏性神经系统疾病，其特征为自闭症、语言技能丧失、刻板行为、运动延迟、认知缺陷、癫痫发作和呼吸异常。大多数病例是由MeCP 2蛋白的突变或缺失引起的，MeCP 2是一种与DNA的甲基化CpG区域结合的转录因子。小鼠中MeCP 2的敲除重现了许多Rett表型，并且成年小鼠神经元中MeCP 2的重新表达纠正了表型缺陷，这表明在疾病发展后给予的治疗可能在治疗上是可行的。然而，患有MeCP 2复制综合征的儿童也表现出明显的Rett样症状，表明MeCP 2的精确水平对于维持正常的神经元功能至关重要。 我们已经发现，编码代谢型谷氨酸受体7（GRM 7/mGlu 7），一种调节谷氨酸和GABA释放的受体的基因，在体外和体内Mecp 2敲除小鼠模型中都受到MeCP 2的正调控。重要的是，我们发现Mecp 2 KO小鼠多个脑区的mGlu 7 mRNA和蛋白水平显著降低。这些结果表明GRM 7基因似乎是MeCP 2的真实和新的靶标。如果正确，我们预测mGlu 7水平将在过度表达MeCP 2的小鼠中升高，这代表了MeCP 2复制综合征的模型。由于mGlu 7激活的一个功能是减少突触前末梢的谷氨酸释放，我们假设Mecp 2 KO小鼠中mGlu 7水平的异常降低增强了谷氨酸能张力。在Mecp 2 KO、敲入和过表达小鼠中已经证明，Schaffer侧支-CA 1（SC-CA 1）突触的突触传递以及长时程增强发生改变。有趣的是，在每种情况下的损害似乎是介导的，在一定程度上，由突触前机制，与小鼠缺乏Mecp 2表现出减少配对脉冲易化，观察一致的增加谷氨酸释放突触前终端。相反，过表达Mecp 2的小鼠显示成对脉冲比增加，表明谷氨酸释放减少。由于mGlu 7是成年动物中SC-CA 1突触处存在的主要mGlu，因此神经传递中的这些缺陷，加上我们发现Mecp 2 KO小鼠中mGlu 7水平降低，与突触前mGlu 7作为SC-CA 1突触处谷氨酸释放的主要控制器的作用一致，可能导致在这些动物中观察到的认知缺陷。我们已经证实了先前的结果，表明突触可塑性和长时程增强在Mecp 2-/y小鼠中改变，并且重要的是，mGlu 7活性的增强可以挽救这些缺陷。我们建议测试的假设，mGlu 7水平相反增加的MeCP 2复制小鼠模型，进一步证实了MeCP 2在mGlu 7基因调控的作用。此外，我们将测试的假设，使用药理学工具的mGlu 7活性的调制将正常化的突触可塑性和行为缺陷下和过表达的MeCP 2蛋白的小鼠。