Translation, Synchrony, and Cognition

翻译、同步和认知

基本信息

批准号：
9460176
负责人：
ANDRE ANTONIO FENTON
金额：
$ 7.16万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-22 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9460176
关键词：
Abnormal coordination Action Potentials Acute Adult Autistic Disorder BC1 RNA Basic Science Behavior Control Behavioral Binding Biological Neural Networks Brain Clinical Cognition Cognitive Cognitive deficits Complex Coupling Data Dendrites Dependence Development Electrodes Electroencephalography FMR1 Failure Fragile X Syndrome Frequencies Functional disorder Goals Hippocampus (Brain)Home environment Impaired cognition Impairment Knock-in Knock-out Knockout Mice Knowledge Learning Link Mediating Memory Mental Depression Mental Retardation Mental disorders Metabotropic Glutamate Receptors Molecular Mus Mutant Strains Mice Neurons Pharmacology Positioning Attribute Protein Biosynthesis RNA RNA-Binding Proteins Research Sampling Schizophrenia Signal Transduction Site Source Synapses System Translational Regulation Translations autistic behaviour base cognitive control density excitatory neuron executive function functional loss information processing inhibitory neuron memory recall mouse model mutant mutant mouse model neural circuit neuronal excitability operation public health relevance receptor relating to nervous system response social cognition

项目摘要

DESCRIPTION (provided by applicant): The synthesis of proteins in synapto-dendritic domains is tightly regulated but in fragile X mental retardation (FXS) and related cases of autism, translation at dendrites is dysregulated due to the loss of at least one regulatory mechanism, the fragile X mental retardation protein (FMRP). How this dysregulation of translation contributes to the clinical expression of impaired cognition in FXS and autism is unknown. An important clue and departure point for formulating our central hypothesis is the fact that loss of FMRP promotes hyperexcitability of neural circuits through overstimulation of group I metabotropic glutamate receptors (mGluR). Group I mGluR-dependent responses increase neuronal excitability and are a necessary determinant of the gamma band (30-100 Hz) electrical oscillations that coordinate action potential discharge throughout the vast networks of excitatory and inhibitory neurons that is the substrate for cognition. Our central "discoordination" hypothesis is that dysregulated translation causes cognitive impairments in FXS and autism because dysregulated translation leads to exaggerated group I mGluR responses that produce inappropriately coordinated synchronization and desynchronization of the electrical activity in the networks of neurons that mediate cognitive information processing in the mammalian brain. This hypothesis is based on advances in the basic science of cognition and the recognition that abnormal neural synchrony is emerging as the core pathophysiology underlying cognitive impairments in mental disorders, including schizophrenia, depression, FXS, and autism. We propose to characterize neural synchrony and cognition in five mutant mouse models of dysregulated RNA translation. In three Specific Aims, we examine neural synchrony in mice lacking the FMRP gene Fmr1, mice lacking BC1 RNA, a second repressor of translation in the brain, and mice lacking both FMRP and BC1 RNA. To confirm that abnormalities arise from acute loss of translation repressors (as predicted by the discoordination hypothesis) and not due to developmental effects, we will use a conditional Fmr1 knockout mutant mouse model that has lost FMRP only in adulthood as well as an inducible knock-in Fmr1 mutant mouse model in which Fmr1 is restored in adulthood under experimental control. First, we investigate abnormalities in the cortical EEG of the mice and determine the dependence on group I mGluR, M1 and 5-HT2 signaling. Second, we investigate neural coordination abnormalities in hippocampus and their synapse-specific origins using linear arrays of electrodes and pharmacological manipulations. Third, we identify which abnormalities coincide with cognitive impairments in the mutant mice. It is our overall goal to determine how translational dysregulation contributes to associated abnormalities in neural synchrony and cognition in fragile X mental retardation and autism.

描述（由申请人提供）：突触树突状结构域中蛋白质的合成受到严格调节，但在脆弱的X智力低下（FXS）和相关的自闭症病例中，树突上的翻译在树突上的翻译失调由于至少一种调节性机制而失去了脆弱的X心理阻滞蛋白（FMRP）。这种翻译的失调如何导致FXS和自闭症认知受损的临床表达是未知的。制定我们的中心假设的一个重要线索和出发点是，FMRP的丧失通过过度刺激I组的A型替代性谷氨酸受体（MGLUR）来促进神经回路的过度兴奋。 I组MGLUR依赖性响应提高了神经元兴奋性，并且是伽马条带（30-100 Hz）电振荡的必要决定因素，该振荡能够协调整个兴奋性和抑制性神经元网络，这是认知的底物。我们的中心“脱节”假设是，失调的翻译失调会导致FXS和自闭症的认知障碍，因为失调的翻译失调会导致夸张的I组响应，从而导致不适当地协调同步和介导的神经元网络中介导的介导性认知信息处理中的电动性信息的同步和降低的响应。哺乳动物的大脑。该假设是基于认知基础科学的进步以及对异常神经同步的认识正在成为精神疾病中认知障碍的核心病理生理学，包括精神分裂症，抑郁症，FXS和自闭症。我们建议在五个失调的RNA翻译失调的突变小鼠模型中表征神经同步和认知。在三个特定目标中，我们检查了缺乏FMRP基因FMR1的小鼠，缺乏BC1 RNA的小鼠，大脑中的第二个翻译抑制剂，而缺乏FMRP和BC1 RNA的小鼠。为了确认异常是由翻译阻遏物的急性丧失（如脱节假说所预测的）而不是由于发育效应所致，我们将使用条件FMR1敲除突变小鼠模型，该模型仅在成熟度中损失了FMRP，并且在诱导的敲入FMR1突变小鼠模型中，FMR1在FMR1中均经过了FMR1的实验。首先，我们研究了小鼠皮质脑袋中的异常，并确定对I组MGLUR，M1和5-HT2信号的依赖性。其次，我们使用电极和药理学操纵的线性阵列研究了海马及其突触特异性起源的神经协调异常。第三，我们确定哪些异常与突变小鼠的认知障碍一致。我们的总体目标是确定翻译失调如何促进脆弱X智力低下和自闭症的神经同步和认知的相关异常。