Synaptic pathophysiology of the 16p11.2 microdeletion mouse model

16p11.2 微缺失小鼠模型的突触病理生理学

基本信息

批准号：
9032540
负责人：
Mark F Bear
金额：
$ 53.1万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9032540
关键词：
16p11.2 Address Affect Animal Model Autistic Disorder Avoidance Learning Behavior Behavioral Behavioral Assay Biochemical Biochemistry Brain Cancer Therapy Evaluation Program Cell physiology Characteristics Chronic Clinical Cognition Cognitive Cognitive deficits Controlled Study Copy Number Polymorphism Data Discrimination Disease Electrophysiology (science)Etiology Exhibits FDA approved Fragile X Syndrome Functional disorder Gene Dosage Gene Mutation Genes Genetic Predisposition to Disease Health Hippocampus (Brain)Human Human Chromosomes Impaired cognition Intellectual functioning disability Intervention Knowledge Learning Light Location Long-Term Depression Lovastatin Measurement Measures Mediating Memory Memory impairment Mendelian disorder Mental disorders Messenger RNA Methods Modeling Molecular Monitor Mus Mutation N-Methyl-D-Aspartate Receptors Pathogenesis Pathway Analysis Patients Pharmaceutical Preparations Pharmacotherapy Phenocopy Phenotype Physiological Processes Physiology Process Protein Biosynthesis Regulation Research Ribosomes Schizophrenia Signal Pathway Signal Transduction Signaling Protein Slice Synapses Synaptic Transmission Synaptic plasticity Testing Therapeutic Tuberous Sclerosis Tuberous sclerosis protein complex Work autism spectrum disorder base cognitive function hippocampal pyramidal neuron interest metabotropic glutamate receptor 5 microdeletion mouse model neuropsychiatry positive allosteric modulator research study

项目摘要

DESCRIPTION (provided by applicant): Currently there are no mechanism-based therapies available for autism spectrum disorders (ASDs) and intellectual disability (ID). The main barrier has been identifying the defective cellular processes within the brain that disrupt behavior and cognition. Increasing evidence indicates that many cases of ASD and ID have a genetic etiology. However, these genetic changes are numerous, often very rare, and remarkably diverse. One way to make sense of these findings is to assume that a plethora of gene mutations may similarly disrupt a common set of physiological processes that ultimately manifest behaviorally as ID and ASD. Testing this assumption is of paramount importance, as not only does it narrow the search for mechanisms of disease pathogenesis, but it also suggests therapeutic strategies that might apply broadly to an entire class of etiologies. Work on animal models of single-gene disorders associated with ID and ASD has supported the idea that one axis of pathophysiology is metabotropic glutamate receptor 5 (mGluR5) mediated synaptic protein synthesis and plasticity. In the animal model of fragile X syndrome (FX), mGluR5-mediated protein synthesis and plasticity in the hippocampus are exaggerated. Conversely, in the animal model of tuberous sclerosis complex (TSC), protein synthesis and plasticity downstream of mGluR5 are diminished. Of particular interest, inhibition of mGluR5 corrects cognitive (and many other) deficits in the FX model, whereas positive modulation of mGluR5 corrects cognitive defects in the TSC model. In the current work, we are asking if gene copy number variation at human chromosome 16p11.2, a polygenic cause of psychiatric illness that can include ID and ASD, similarly disrupts this core synaptic mechanism. This hypothesis is suggested by the findings that many genes in the affected region are predicted to be involved in protein synthesis regulation, and preliminary data in the mouse model of 16p11.2 microdeletion showing disrupted mGluR5-mediated synaptic plasticity and cognitive function, and correction of memory deficits by chronic inhibition of mGluR5. The specific aims of our proposed research are to (a) further characterize the state of synaptic transmission and plasticity in the hippocampus of 16p11.2 CNV model mice, (b) characterize synaptic protein synthesis and the molecular signaling pathways which may be disrupted in these mice, (c) further assess the behavioral deficits in 16p11.2 CNV model mice, and (d) attempt to correct memory deficits with rational pharmacotherapies previously validated in animal models of FX and TSC.

描述（由适用提供）：目前尚无基于机制的疗法可用于自闭症谱系障碍（ASD）和智力障碍（ID）。主要的障碍是确定破坏行为和认知的大脑内部缺陷的细胞过程。越来越多的证据表明，许多ASD和ID病例具有遗传病因。但是，这些遗传变化众多，通常非常罕见，并且非常多样化。理解这些发现的一种方法是假设大量基因突变可能会类似地破坏一组共同的物理过程，这些过程最终在行为上表现为ID和ASD。测试这一假设至关重要，因为它不仅可以缩小搜索疾病发病机理的搜索，而且还提出了可能广泛适用于整个病因的治疗策略。与ID和ASD相关的单基因疾病的动物模型的工作支持了这样一个观念，即病理生理学的一个轴是代谢型谷氨酸受体5（MGLUR5）介导的合成蛋白合成和可塑性。在脆弱X综合征（FX）的动物模型中，夸张了海马中MGLUR5介导的蛋白质合成和可塑性。相反，在结节性硬化症复合物（TSC）的动物模型中，Mglur5下游的蛋白质合成和可塑性减少。特别有趣的是，对MGLUR5的抑制纠正了FX模型中的认知（和许多其他）定义，而MGLUR5的正调制纠正了TSC模型中的认知缺陷。在当前的工作中，我们询问人类16p11.2的基因拷贝数变化是否是精神疾病的多基因原因，可以包括ID和ASD，同样会破坏这种核心突触机制。这一发现提出了这一假设，该发现表明，受影响区域中的许多基因被预测与蛋白质合成调节有关，并且在16p11.2小鼠模型中的初步数据微骨骼模型显示了MGLUR5介导的MGLUR5介导的同意可变功能和认知功能中断，并通过慢性抑制MGLUR 5。我们提出的研究的具体目的是（a）进一步表征16p11.2 CNV模型小鼠海马中突触传播和可塑性的状态，（b）表征合成蛋白合成的特征，以及在这些小鼠中可能破坏的分子信号通路，并进一步评估这些行为（c）在16p11.2 c11.2 c11.2 c11.2 c11.2 c11.2 c11.2 c11.2 c11.2 c11.2 c11.2 c11 v的模型中（c）先前在FX和TSC动物模型中验证的药物疗法。