Translation, Synchrony, and Cognition

翻译、同步和认知

• 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
• 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

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(申请人提供)：突触-树突域中蛋白质的合成受到严格调控，但在脆性X智力低下(FXS)和相关的自闭症病例中，由于至少一个调节机制--脆性X智力低下蛋白(FMRP)的缺失，树突上的翻译受到失调。这种翻译失调如何导致FXS和自闭症患者认知受损的临床表现尚不清楚。提出我们的中心假说的一个重要线索和出发点是，FMRP的缺失通过过度刺激I组代谢性谷氨酸受体(MGluR)而促进神经回路的超兴奋性。I组mGluR依赖的反应增加了神经元的兴奋性，是伽马频段(30-100赫兹)电振荡的必要决定因素，伽马频段电振荡协调动作电位放电，整个庞大的兴奋性和抑制性神经元网络是认知的底物。我们的中心“不协调”假设是，翻译失调会导致FXS和自闭症患者的认知障碍，因为翻译失调会导致I组mGluR反应被夸大，从而导致神经元网络中参与认知信息处理的神经元网络中的电活动不适当地协调同步和去同步 哺乳动物的大脑。这一假说是基于认知科学的进展和认识到异常神经同步性正在成为精神障碍(包括精神分裂症、抑郁症、FXS和自闭症)认知障碍的核心病理生理学。我们建议在五个RNA翻译异常的突变小鼠模型中表征神经同步性和认知。在三个特定的目标中，我们检查了缺乏FMRP基因Fmr1的小鼠，缺乏脑中翻译的第二抑制因子BC1RNA的小鼠，以及缺乏FMRP和BC1RNA的小鼠。为了证实异常是由翻译抑制物的急性丢失引起的(如不协调假说所预测的)，而不是由于发育影响，我们将使用只有在成年时才失去Fmr1的条件性Fmr1基因敲除突变小鼠模型，以及在实验控制下在成年后恢复Fmr1的可诱导敲入Fmr1突变小鼠模型。首先，我们研究了小鼠皮质脑电的异常，并确定了对I组mGluR、M1和5-HT2信号的依赖。其次，我们使用线性电极阵列和药物操作来研究海马区的神经协调异常及其突触特异性起源。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导致脆性X智力低下和自闭症患者神经同步性和认知的相关异常。