The age-dependence of synaptic deficits in 22q11.2 deletion syndrome mouse models

22q11.2缺失综合征小鼠模型突触缺陷的年龄依赖性

• 批准号: 9304348
• 负责人: Laurie R Earls
• 金额: $ 23.84万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304348
• 关键词: 22q11; 22q11 Deletion Syndrome; ATP phosphohydrolase; Adolescence; Adolescent; Adult; Affect; Age; Anabolism; Binding; Binding Proteins; Binding Sites; Biochemical; Biological Assay; Brain; Calcium; Chromosome Arm; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 22; Cognitive deficits; Comorbidity; Complex; Defect; Dependence; Development; Disease; Disease model; Endoplasmic Reticulum; Event; Foundations; Genes; Genomics; Germ Lines; Goals; Heart; Hippocampus (Brain); Human; Impaired cognition; K-Series Research Career Programs; Laboratories; Learning Disabilities; Literature; Long-Term Potentiation; Measures; Memory impairment; Mental disorders; Methods; MicroRNAs; Modeling; Molecular; Mus; Mutant Strains Mice; Onset of illness; Pathway interactions; Patients; Phenocopy; Phenotype; Play; Preparation; Proteins; Proteomics; Pump; RNA; Research; Reticulum; Risk; Schizophrenia; Symptoms; Synapses; Synaptosomes; Syndrome; Techniques; Testing; Thymus Gland; Time; Transcript; Translations; Up-Regulation; Work; age related; cognitive ability; conotruncal anomaly face syndrome; craniofacial; design; disease phenotype; ds RNA-Binding Proteins; early onset; emerging adult; experimental study; genetic predictors; in vivo; in vivo Model; interest; juvenile animal; knock-down; microdeletion; mouse model; mutant; neurotransmitter release; overexpression; presynaptic; programs; psychiatric symptom; relating to nervous system; spatial memory

DESCRIPTION (provided by applicant): The 22q11 micro-deletion syndrome is characterized by the age-dependent onset of various psychiatric diseases, including a 30% chance of developing schizophrenia. We have previously discovered an age- dependent increase in long term potentiation (LTP) in the hippocampus of mouse models of 22q11DS. Increased LTP correlates with memory deficits in these mice. Both LTP increase and cognitive deficits become evident in early adulthood. Since the deletion is present in the germ line, it is not clear why these deficits emerge so late in development. The goal of this proposal is to understand the age-dependence of neural deficits in mouse models of 22q11DS. Our recent work showed that the micro-deletion gene Dgcr8 is important for increased LTP. Dgcr8 is a double-stranded RNA binding protein important for microRNA biosynthesis. Heterozygous loss of Dgcr8 results in the depletion of specific miRNAs (miR-25 and miR-185) which target the expression of the Sarco/endoplasmic reticular ATPase (Serca2), a protein which pumps Ca2+ into the ER. Reducing these miRNAs results in the increased expression of Serca2 and over-filling of the ER with Ca2+. The resulting alteration in synaptic Ca2+ dynamics is responsible for the observed increase in LTP in Dgcr8+/- mice. Since Dgcr8 and miRNAs are reduced from the beginning of development, however, it is not clear why Serca2 upregulation and LTP deficits appear only in early adulthood. We propose 3 possible mechanisms for age-dependent control of Serca2 expression by miRNAs in these mouse models. First, miRNAs of interest may be normally reduced with age, and the deletion may further deplete them below a phenotypic threshold. Second, the localization of the miRNA-Serca2 pathway may change with development, becoming more important at the synapse with age. Finally, the sensitivity of the Serca2 transcript to these miRNAs may change with age. Several examples of translation that is locally controlled at the synapse now exist in the literature. The packaging of a given transcript in protein and RNA complexes can influence its exposure or sensitivity to miRNAs. Since these 3 mechanisms are not mutually exclusive, one or more of them may be at play in the age-dependence of miRNAs' effects on the Serca2 transcript. This study will further clarify a pathway that could be important for the treatment of both 22q11DS and schizophrenia patients. Little is understood about the molecular events important for the development of the human brain during late adolescence and early adulthood, though multiple psychiatric diseases emerge during this period. This proposal outlines a specific study of one molecular pathway that appears to be developmentally regulated and important for disease onset during this stage. Further study of normal and disease development during this critical developmental stage will be the foundation for launching my own laboratory. The career development award would be an important step in establishing this research program.

描述（由申请人提供）：22q11微缺失综合征的特征是各种精神病患者的年龄依赖性发作，包括患有精神分裂症的30％机会。我们以前已经发现在22q11ds小鼠模型的海马中，长期增强（LTP）的年龄依赖性增加。增加的LTP与这些小鼠的记忆缺陷相关。 LTP的增加和认知缺陷在成年初都显而易见。由于删除存在于细菌系中，因此尚不清楚为什么这些缺陷在开发中如此晚期出现。该建议的目的是了解22q11ds小鼠模型中神经缺陷的年龄依赖性。我们最近的工作表明，微缺失基因DGCR8对于增加LTP很重要。 DGCR8是一种对microRNA生物合成重要的双链RNA结合蛋白。 DGCR8的杂合损失导致特异性miRNA（miR-25和miR-185）的耗竭，该蛋白质的蛋白质是sarco/sarco/内质网ATPase（SERCA2）的表达，这是一种将Ca2+泵入ER中的蛋白质。减少这些miRNA会导致SERCA2表达增加，而ER用Ca2+过度填充。突触CA2+动力学的结果改变是导致观察到的DGCR8 +/-小鼠LTP增加的。但是，由于DGCR8和miRNA从开发开始就减少了，因此尚不清楚为什么SERCA2上调和LTP缺陷仅在成年初才出现。我们提出了3种可能的机制，用于在这些小鼠模型中miRNA对SERCA2表达的年龄依赖性控制。首先，感兴趣的miRNA通常会随着年龄的增长而减少，并且缺失可能会进一步耗尽表型阈值以下。其次，miRNA-serca2途径的定位可能随发育的变化而变化，随着年龄的增长而变得越来越重要。最后，SERCA2转录物对这些miRNA的敏感性可能随着年龄的增长而变化。文献中现在存在着在突触中局部控制的几个翻译示例。蛋白质和RNA复合物中给定转录本的包装可以影响其对miRNA的暴露或敏感性。由于这三种机制不是相互排斥的，因此其中一种或多种可能在miRNA对SERCA2转录本的影响的年龄依赖性中起作用。这项研究将进一步阐明一条对于治疗22Q11D和精神分裂症患者的途径。关于在青春期和成年初期对人脑发展重要的分子事件，尽管在此期间出现了多种精神病，但对人脑的发展很重要。该提议概述了一项针对一个分子途径的特定研究，该研究似乎在发育中受到调控，对于此阶段的疾病发作很重要。在这个关键发展阶段，对正常和疾病发展的进一步研究将是推出我自己的实验室的基础。职业发展奖将是建立该研究计划的重要一步。