Synapse Remodeling in Mecp2 Mouse Models

Mecp2 小鼠模型中的突触重塑

• 批准号: 7586864
• 负责人: Chinfei Chen
• 金额: $ 25.5万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586864
• 关键词: Address; Affect; Alanine; Behavior; Biological Assay; Biological Models; Birth; Brain; Child; Data; Defect; Dendritic Spines; Development; Developmental Process; Disease; Employee Strikes; Exhibits; Experimental Models; Eye; Future; Genes; Genetic; Goals; Grant; In Vitro; Knock-in Mouse; Knock-out; Laboratories; Maintenance; Mental Retardation; Methyl-CpG-Binding Protein 2; Modification; Morphology; Mus; Mutant Strains Mice; Mutation; Neurodevelopmental Disorder; Neurons; Phase; Phenotype; Phosphorylation; Process; Proteins; Refractory; Regulation; Relative (related person); Retinal; Retinal Ganglion Cells; Rett Syndrome; Role; Seizures; Sensory; Series; Serine; Site; Social Interaction; Staging; Synapses; Synaptic plasticity; Techniques; Testing; Thalamic structure; Therapeutic Intervention; Time; Transcription Repressor/Corepressor; Visual; autism spectrum disorder; design; experience; follow-up; girls; in vivo; mouse model; neural circuit; neuropsychiatry; public health relevance; response; retinogeniculate; synaptic function; vision development; visual deprivation

DESCRIPTION (provided by applicant): Rett Syndrome (RTT) is a genetic neurodevelopmental disorder in girls affecting 1 in 10,000 births that is characterized by mental retardation, seizures, repetitive behaviors and abnormalities in social interactions. Mutations in the methyl-CpG-binding protein 2 gene (MECP2) have been found to be responsible for the majority of cases of RTT. A striking feature of this disorder is the initial apparent normal development that is followed by a regression in communicative and locomotive abilities. There is growing evidence that synaptic connections are abnormal in RTT. However, the phase at which synapse development that is disrupted is still unclear. Are synapses formed incorrectly from the start? Or do synapses form normally, but then fail to strengthen appropriately? Is the refinement process by which excess connections are eliminated abnormal? Or after normal development, does the brain fail to maintain synapses properly? To address these questions, we propose to study synaptic function during development of the visual thalamus in Mecp2 mutant mice, mouse models for the study of RTT. One model system in which a series of functional developmental phases is well characterized is the retinogeniculate synapse, the connection between retinal ganglion cells in the eye and relay neurons in the visual thalamus, making this a good assay for synapse development. Using electrophysiological techniques, we have previously shown that development of this synapse involves three distinct phases. After the first phase in development, when synapses are initially formed, there are two subsequent periods of intense synaptic remodeling. The second phase of development occurs around the time of eye opening when some retinal inputs to a given relay neuron are strengthened while other inputs are eliminated. A third phase occurs later in development when changes in sensory experience can activate the remodeling of synaptic connections, a process thought to be necessary for the adaptation of synaptic circuits to sensory experience. Here, we will examine synapse development in two Mecp2 mouse models for RTT, one in which the entire Mecp2 gene is disrupted (Mecp2-/y), and the other in which the Ser421 residue of the endogenous MeCP2 protein, a site of neuronal activity-dependent modification, has been replaced with an alanine residue (Mecp2S421A/y). Phosphorylation of this serine has previously been implicated in the regulation of dendritic and spine morphology in vitro. We will test two hypotheses: 1) Disruption of the normal response to sensory experience underlies the developmental regression observed in RTT, and 2) that this phase in synapse development is regulated by phosphorylation of the Ser421 residue of the MeCP2 protein. Thus we will evaluate synaptic strength and connectivity over development and in response to changes in sensory experience. This information, in turn, will guide our future design of therapeutic interventions for children with RTT. PUBLIC HEALTH RELEVANCE: In this grant we propose to study the formation of synaptic circuits in Mecp2 mouse models for Rett Syndrome and other Autism Spectrum Disorders. By identifying the stage of synapse development that is disrupted in Mecp2 mice, we can begin to elucidate the mechanisms that are important in normal synapse development. Moreover, by characterizing the potential plasticity of these synapses in Mecp2 mice, we will test whether synaptic circuits in these mouse models can be rewired to correct for abnormal synaptic connections. The results from these studies may help guide the design future therapies for Rett Syndrome and Autism Spectrum Disorders.

描述（由申请人提供）：RETT综合征（RTT）是一种遗传神经发育障碍，在影响10,000只分娩中有1个的女孩，其特征是社交互动中精神障碍，癫痫发作，重复行为和异常。发现甲基-CPG结合蛋白2基因（MECP2）的突变是导致大多数RTT病例的原因。这种疾病的一个惊人特征是最初的明显正常发育，随后是交流和机车能力的回归。越来越多的证据表明突触连接在RTT中是异常的。但是，破坏突触发展的阶段尚不清楚。从一开始就不正确地形成了突触吗？还是正常形成突触，但无法适当地加强？是否消除了过多连接异常的完善过程？还是正常发育后，大脑是否无法正确保持突触？为了解决这些问题，我们建议在MECP2突变小鼠的视觉丘脑开发过程中研究突触功能，RTT研究的小鼠模型。一系列功能发育阶段的一个模型系统是视网膜生成突触，眼睛中的视网膜神经节细胞与视觉丘脑中的中继神经元之间的联系，这是突触发育的良好测定法。使用电生理技术，我们以前已经表明，该突触的发展涉及三个不同的阶段。在开发第一阶段之后，当最初形成突触时，有两个随后的激烈突触重塑。开发的第二阶段发生在开眼界的时间左右，当时某些视网膜输入加强了给定的继电器神经元，而消除了其他输入。当感觉体验的变化可以激活突触连接的重塑时，第三阶段发生在开发中，这是将突触电路适应感官体验所必需的过程。在这里，我们将检查两个用于RTT的MECP2小鼠模型中的突触发展，其中一个MECP2基因被中断（MECP2-/Y），而另一种Mecp2-/Y），另一个MECP2 MECP2蛋白的Ser421残基是神经元活性依赖性依赖神经元的修饰的位点的残基，已替换为Alanine y/yecp2s/MeCP2S42S422S42S42A.42A2。以前，该丝氨酸的磷酸化与体外树突状和脊柱形态的调节有关。我们将检验两个假设：1）在RTT中观察到的发育回归的正常反应的破坏，以及2）突触发育中的这种阶段受MECP2蛋白的Ser421残基的磷酸化调节。因此，我们将评估突触强度和连通性在发展上，并响应感官体验的变化。反过来，这些信息将指导我们对RTT儿童的治疗干预措施的未来设计。公共卫生相关性：在这笔赠款中，我们建议研究RETT综合征和其他自闭症谱系的MECP2小鼠模型中突触电路的形成。通过识别MECP2小鼠中破坏的突触发展阶段，我们可以开始阐明在正常突触发育中很重要的机制。此外，通过表征MECP2小鼠中这些突触的潜在可塑性，我们将测试这些小鼠模型中的突触电路是否可以重新连接以校正异常的突触连接。这些研究的结果可能有助于指导RETT综合征和自闭症谱系疾病的未来设计疗法。