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

基本信息

批准号：
9113112
负责人：
Laurie R Earls
金额：
$ 24.84万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113112
关键词：
22q11 22q11 Deletion Syndrome 22q11.2 ATP phosphohydrolase Adolescence Adolescent Adult Affect Age Anabolism Binding Binding Sites Biochemical Biological Assay Brain Calcium Chromosomes, Human, Pair 16 Chromosomes, Human, Pair 22 Cognitive deficits Complex Congenital chromosomal disease Defect Dependence Development Disease Disease model Down Syndrome Endoplasmic Reticulum Event Foundations Gene Deletion Genes Genomics Germ Lines Goals Health Heart Hippocampus (Brain)Homologous Gene Human Human Development Impaired cognition K-Series Research Career Programs Laboratories Lead Learning Disabilities Light Literature Long-Term Potentiation Measures Memory impairment Mental disorders Methods MicroRNAs Modeling Molecular Mus Mutant Strains Mice Neuronal Dysfunction Onset of illness Pathway interactions Patients Phenocopy Phenotype Play Population Preparation Probability Proteins Proteomics Pump RNA RNA-Binding Proteins Research Reticulum Risk Schizophrenia Staging Symptoms Synapses Syndrome Techniques Testing Time Transcript Translations Up-Regulation Work age related arm cognitive ability craniofacial design disease phenotype ds RNA-Binding Proteins early onset emerging adult genetic predictors in vivo in vivo Model interest juvenile animal knock-down microdeletion mouse model mutant neurotransmitter release novel overexpression presynaptic programs relating to nervous system research study spatial memory

项目摘要

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 微缺失综合征的特点是各种精神疾病的发病年龄依赖性，包括 30% 的几率发展为精神分裂症。我们之前发现 22q11DS 小鼠模型海马的长时程增强 (LTP) 呈年龄依赖性增加。 LTP 增加与这些小鼠的记忆缺陷相关。 LTP 增加和认知缺陷在成年早期变得明显。由于缺失存在于种系中，因此尚不清楚为什么这些缺陷在发育过程中出现得这么晚。该提案的目标是了解 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 LTP 的增加很重要。 Dgcr8 是一种对 microRNA 生物合成很重要的双链 RNA 结合蛋白。 Dgcr8 的杂合缺失会导致特定 miRNA（miR-25 和 miR-185）的缺失，这些 miRNA 的目标是 Sarco/内质网状 ATP 酶 (Serca2) 的表达，Serca2 是一种将 Ca2+ 泵入内质网的蛋白质。减少这些 miRNA 会导致 Serca2 表达增加以及内质网被 Ca2+ 过度填充。由此产生的突触 Ca2+ 动力学变化是 Dgcr8+/- 小鼠中观察到的 LTP 增加的原因。然而，由于 Dgcr8 和 miRNA 从发育之初就减少，因此尚不清楚为什么 Serca2 上调和 LTP 缺陷仅出现在成年早期。我们提出了 3 种可能的机制，用于在这些小鼠模型中通过 miRNA 对 Serca2 表达进行年龄依赖性控制。首先，感兴趣的 miRNA 通常可能会随着年龄的增长而减少，并且缺失可能会进一步将它们消耗到表型阈值以下。其次，miRNA-Serca2 通路的定位可能会随着发育而改变，随着年龄的增长在突触中变得更加重要。最后，Serca2 转录本对这些 miRNA 的敏感性可能会随着年龄的增长而变化。现在文献中存在几个在突触局部控制翻译的例子。蛋白质和 RNA 复合物中给定转录本的包装会影响其对 miRNA 的暴露或敏感性。由于这 3 种机制并不相互排斥，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发挥作用。这项研究将进一步阐明一条对于 22q11DS 和精神分裂症患者的治疗可能很重要的途径。尽管在此期间出现了多种精神疾病，但人们对青春期晚期和成年早期对人脑发育重要的分子事件知之甚少。该提案概述了对一个分子途径的具体研究，该分子途径似乎受到发育调节，并且对于这一阶段疾病的发生很重要。对这个关键发育阶段的正常和疾病发育的进一步研究将是建立我自己的实验室的基础。职业发展奖将是建立该研究项目的重要一步。