Translation, Synchrony, and Cognition

翻译、同步和认知

• 批准号: 9179660
• 负责人: ANDRE ANTONIO FENTON
• 金额: $ 38万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-18 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9179660
• 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（由申请人提供）：突触树突结构域中的蛋白质合成受到严格调节，但在脆性 X 智力迟钝（FXS）和相关自闭症病例中，树突的翻译由于至少一种调节机制（脆性 X 智力迟钝蛋白（FMRP））的缺失而失调。这种翻译失调如何导致 FXS 和自闭症认知受损的临床表现尚不清楚。 制定我们的中心假设的一个重要线索和出发点是，FMRP 的缺失会通过过度刺激 I 类代谢型谷氨酸受体 (mGluR) 来促进神经回路的过度兴奋。 I 组 mGluR 依赖性反应会增加神经元兴奋性，并且是伽马带 (30-100 Hz) 电振荡的必要决定因素，伽马带电振荡协调整个兴奋性和抑制性神经元庞大网络的动作电位放电，而兴奋性和抑制性神经元是认知的基础。 我们的中心“失调”假设是，翻译失调会导致 FXS 和自闭症的认知障碍，因为翻译失调会导致 I 组 mGluR 反应夸大，从而在介导认知信息处理的神经元网络中产生不适当协调的电活动同步和去同步。 哺乳动物的大脑。这一假说基于认知基础科学的进步，以及人们认识到异常神经同步正在成为精神疾病（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基础。我们建议表征五种 RNA 翻译失调的突变小鼠模型的神经同步性和认知能力。在三个具体目标中，我们检查了缺乏 FMRP 基因 Fmr1 的小鼠、缺乏 BC1 RNA（大脑中第二种翻译抑制因子）的小鼠以及同时缺乏 FMRP 和 BC1 RNA 的小鼠的神经同步性。为了确认异常是由翻译抑制子的急性缺失引起的（如不协调假说所预测的），而不是由于发育影响，我们将使用仅在成年期失去 FMRP 的条件性 Fmr1 敲除突变小鼠模型，以及诱导性敲入 Fmr1 突变小鼠模型，其中 Fmr1 在成年期在实验控制下恢复。首先，我们研究小鼠皮质脑电图的异常并确定对 I 组 mGluR、M1 和 5-HT2 信号传导的依赖性。其次，我们使用线性电极阵列和药理操作研究海马体的神经协调异常及其突触特异性起源。第三，我们确定了哪些异常与突变小鼠的认知障碍相符。我们的总体目标是确定翻译失调如何导致脆性 X 智力低下和自闭症的神经同步和认知异常。