Deciphering the Roles of Kainate Receptors in Developing CNS Circuits

解读红藻氨酸受体在发展中枢神经系统回路中的作用

基本信息

批准号：
9904784
负责人：
Anis Contractor
金额：
$ 51.72万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904784
关键词：
Ataxia Behavior Behavioral Brain region Child Childhood Chlorides Cognitive Communication Comparative Study Contractor Corpus striatum structure Data Dendrites Development Developmental Delay Disorders Disease Equilibrium Etiology Exhibits Face Genes Genetic Genetic Diseases Glutamate Receptor Goals Hippocampus (Brain)Homeostasis Human Human Genetics Intellectual functioning disability Kainic Acid Receptors Knock-out Knowledge Laboratories Lead Long-Term Effects Measures Mediating Missense Mutation Modeling Molecular Molecular Analysis Morphology Motor Mus Mutant Strains Mice Mutation Nature Neuraxis Neurodevelopmental Disorder Neurologic Neurons Neurotransmitter Receptor Phenotype Photometry Physiological Play Population Property Proteome Proxy Receptor Gene Receptor Signaling Regulation Role Shapes Signal Transduction Social Interaction Structure Symptoms Synapses Synaptic Transmission Testing Variant autism spectrum disorder base behavioral phenotyping behavioral study causal variant cellular development cognitive function critical period developmental disease experimental study genetic variant human model in vivo insight interest loss of function loss of function mutation motor disorder mouse model nervous system development neurodevelopment neuron development neuronal circuitry neuronal excitability neurotransmitter release receptor function social stereotypy synaptic function

项目摘要

SUMMARY Kainate receptor signaling is required for the appropriate development of the central nervous system. Children with de novo loss-of-function or missense mutations exhibit intellectual disability and other severe developmental phenotypes. Why this occurs is unknown, in part because we do not have a clear understanding of how aberrant kainate receptor function disrupts neural development. The objectives of this project are to (i) gain insight into normal neurodevelopmental roles played by kainate receptors and (ii) to determine the nature of circuit and behavioral disruptions when kainate receptor signaling is aberrant or completely lost in mouse models. We will pursue these objectives using comparative studies in mice that model known genetic variants causative for human disorders. These include a new mouse line generated in the Swanson laboratory, GluK2(A657T), that models a human de novo missense mutation in the Grik2 gene that causes intellectual disability (ID) and ataxia, as well as mice which model Grik2 haploinsufficiency which is associated with developmental delay and ID in human populations. The Contractor, Swanson and Savas laboratories will use these mice to test the hypotheses that kainate receptors establish an appropriate balance between excitation and inhibition in developing hippocampal circuits, are required for correct development of synapses, and regulate intrinsic excitability in the CNS. In the first Specific Aim, we will determine how missense or loss-of-function mutations in Grik2 alter synaptic connectivity, function, morphology and expression of the synaptic and non-synaptic proteome in brain regions associated with altered behaviors. In the second Specific Aim, we determine how intrinsic excitability is altered in kainate receptor mutant mice. In the third Specific Aim, we will carry out behavioral studies on kainate receptor mutant mice to determine the expanse of cognitive, social, habitual, and motor dysfunction, which will also inform the physiological studies in Aims 1 and 2. We anticipate these studies will reveal some of the underlying circuit disruptions that give rise to human cognitive and motor phenotypes. We therefore aim to develop a comprehensive and integrated understanding of the importance of kainate receptor signaling to establishment of appropriate neuronal function in the CNS and establish how aberrant signaling leads to maladaptive development and behaviors in mice that are correlates of the core symptoms of human developmental disorders.

概括适当发展中枢神经系统需要海藻酸盐受体信号传导。孩子们从头丧失或失误突变表现出智力残疾和其他严重发展表型。为什么发生这种情况是未知的，部分原因是我们没有清晰了解异常海谷酸酯受体功能如何破坏神经发育。目标的目标项目将（i）洞悉海关受体扮演的正常神经发育角色，（ii）确定当海关受体信号异常或在鼠标模型中完全丢失。我们将使用在小鼠中使用比较研究来实现这些目标模型已知的遗传变异性人为疾病。这些包括在 Swanson实验室Gluk2（A657T），该实验室在Grik2基因中建模了从头de的失误突变这会导致智力残疾（ID）和共济失调，以及型号Grik2单倍不足的老鼠与人口中的发育延迟和ID相关。承包商，斯旺森和萨瓦斯实验室将使用这些小鼠来测试海藻酸盐受体建立适当平衡的假设在开发海马电路中的激发和抑制之间，正确开发的开发是必需的突触并调节中枢神经系统的内在兴奋性。在第一个特定目标中，我们将确定如何 GRIK2中的错义或功能丧失突变改变了突触连通性，功能，形态和与行为改变有关的大脑区域中突触和非突触蛋白质组的表达。在第二个特定目的是，我们确定海藻酸盐受体突变小鼠中的内在兴奋性如何改变。在第三个具体目的，我们将对海谷酸酯受体突变小鼠进行行为研究，以确定认知，社会，习惯和运动功能障碍的广泛，这也将为生理研究提供信息目标1和2。我们预计这些研究将揭示一些引起的基础电路中断人类认知和运动表型。因此，我们旨在开发全面而综合的了解海谷酸酯受体信号传导对建立适当神经元功能的重要性在中枢神经系统中，并确定异常信号如何导致小鼠的适应不良的发育和行为，是人类发育障碍的核心症状的相关性。