Translation, Synchrony, and Cognition

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控，但在脆性X智力低下（FXS）和相关自闭症病例中，由于至少一种调控机制（脆性X智力低下蛋白（FMRP））的缺失，树突处的翻译失调。这种翻译的失调如何导致FXS和自闭症中认知受损的临床表现尚不清楚。 一个重要的线索和出发点，制定我们的中心假设是这样一个事实，即FMRP的损失促进过度兴奋的神经回路通过过度刺激组I代谢型谷氨酸受体（mGluR）。I组mGluR依赖性反应增加神经元兴奋性，并且是γ频带（30-100 Hz）电振荡的必要决定因素，所述γ频带电振荡协调作为认知底物的兴奋性和抑制性神经元的庞大网络中的动作电位放电。 我们的中心“失调”假说是失调的翻译导致FXS和自闭症的认知障碍，因为失调的翻译导致夸大的I组mGluR反应，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化。 哺乳动物的大脑这一假说是基于认知基础科学的进步，以及对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的认识。我们建议在五个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Fmr 1的小鼠，缺乏BC 1 RNA（大脑中第二种翻译抑制因子）的小鼠以及缺乏FMRP和BC 1 RNA的小鼠的神经同步性。为了证实异常是由翻译抑制子的急性丢失引起的（如失调假说所预测的），而不是由于发育影响，我们将使用仅在成年期丢失FMRP的条件性Fmr 1敲除突变小鼠模型以及在实验控制下在成年期恢复Fmr 1的诱导性敲入Fmr 1突变小鼠模型。首先，我们研究小鼠皮层EEG的异常，并确定对I组mGluR，M1和5-HT 2信号的依赖性。其次，我们研究神经协调异常的海马和突触的具体起源使用线性阵列的电极和药理学操作。第三，我们确定哪些异常与突变小鼠的认知障碍一致。这是我们的总体目标，以确定如何翻译失调有助于相关异常的神经同步性和认知脆性X智力低下和自闭症。

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.