Translation, Synchrony, and Cognition

描述（由申请人提供）：突触-树突结构域的蛋白质合成受到严格调控，但在脆性X智力发育迟缓（FXS）和相关自闭症病例中，树突翻译由于至少一种调节机制的缺失而失调，即脆性X智力发育迟缓蛋白（FMRP）。这种翻译失调如何导致认知障碍在FXS和自闭症中的临床表现尚不清楚。形成我们中心假设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）来促进神经回路的高兴奋性。第一组mglur依赖的反应增加了神经元的兴奋性，并且是伽马带（30-100 Hz）电振荡的必要决定因素，这种振荡协调了整个兴奋性和抑制性神经元网络的动作电位放电，这是认知的基础。我们的中心“失调”假设是，失调的翻译导致FXS和自闭症的认知障碍，因为失调的翻译导致过度的I组mGluR反应，导致介导大脑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不同步

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.