The role of RNA binding protein in FXR1P in interneurons

RNA结合蛋白在中间神经元FXR1P中的作用

• 批准号: 10023274
• 负责人: Xinyu Zhao
• 金额: $ 46.14万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-24 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023274
• 关键词: Adolescent; Adult; Affect; Anti-Anxiety Agents; Anxiety; Attention; Behavior; Behavioral; Binding; Biological Assay; Brain; Cell Nucleus; Cells; Cognition; Complex; Compulsive Behavior; Data; Development; Exhibits; FMR1; FXR1 gene; Feedback; Frequencies; Gene Expression; Gene Expression Regulation; Genes; Genetic; Histologic; Homologous Gene; Human; Hybrids; Hyperactive behavior; Image; Impairment; Individual; Interneurons; Knockout Mice; Learning; Link; Literature; LoxP-flanked allele; Memory impairment; Mental disorders; Messenger RNA; Methods; MicroRNAs; Molecular; Morphology; Mus; Neonatal; Neurons; Parvalbumins; Pathway Analysis; Perinatal mortality demographics; Periodicity; Physiological; Physiology; Population; Prefrontal Cortex; Property; Prosencephalon; Protein Deficiency; Proteins; RNA Stability; RNA-Binding Proteins; Rabies virus; Regulation; Role; Schizophrenia; Sensory; Sequence Homology; Short-Term Memory; Synapses; Synaptic plasticity; Techniques; Tertiary Protein Structure; Testing; Time; Translations; Validation; Work; autism spectrum disorder; base; behavior change; cognitive function; cohort; excitatory neuron; experimental study; genome wide association study; genome-wide; human disease; information processing; inhibitory neuron; insight; interdisciplinary approach; loss of function; neural circuit; novel; overexpression; patch clamp; postnatal; postnatal development; risk variant; sensor; social; transcriptome; translatome; voltage

Abstract Fragile X related protein 1 (FXR1P) is a brain-enriched RNA binding protein. Its loss of function is intolerant for both mice and humans. Large-scale genome wide association studies and recent gene network analyses have identified FXR1 as a high confidence risk gene for mental illness. FXR1P has unique protein domains and mechanisms of action that are distinct from its X-linked homolog fragile X mental retardation protein. Due to neonatal lethality of FXR1P-null mice the impact of FXR1P deficiency on brain development and postnatal brain function is largely unexplored. FXR1P is widely expressed in both excitatory and inhibitory neurons in the mammalian brain throughout postnatal development and in adults. Limited literature and our preliminary data suggest that FXR1P may have distinct functions in inhibitory versus excitatory neurons. The function of FXR1P in interneurons has not been studied. Complex neuronal information processing depends on precise spatial and temporal coordination of principal excitatory neurons, which requires intimate interactions between excitatory and inhibitory interneurons. Among inhibitory neurons, fast spiking, parvalbumin (PV)-expressing interneurons (PVIs) have emerged as critical players in many forms of circuit activities. PVIs provide both feedback and feedforward inhibition to excitatory neurons and entrain cortical networks to drive gamma oscillations and control their frequency and strength. Extensive studies have shown that gamma oscillations are important for sensory processing, attention, working memory, and cognition, which are impaired in a number of mental disorders, including autism and schizophrenia. However, the regulation of gene expression in PVIs has received limited attention. We found that FXR1P is expressed in a majority of PVIs of adult mouse cortex. Our preliminary data show that mice with PVI-specific deletion of FXR1P exhibited deficits in behaviors that require proper function of prefrontal cortex (PFC). Interestingly, these behavioral changes are not found in mice with FXR1P deletion only in forebrain excitatory neurons. We hypothesize that FXR1P regulates gene expression in PVIs in the PFC to control PVI excitability, synaptic plasticity, and circuit function and FXR1P deficiency in PVIs alters cortical circuit activities leading to behavioral deficits. We will determine whether FXR1P deficiency in PVIs in the PFC leads to deficits in PVI physiology and connectivity, impairs PFC- dependent behaviors, and changes in specific gene networks. This work brings state-of-art techniques together in a multidisciplinary approach to investigate how FXR1P deficiency impacts the function of an important type of interneuron. Our approach provides a potential framework for assessing other potentially important genes with unclear functions, in PVIs and other genetically defined populations of neurons.

摘要 脆性X相关蛋白1（FXR 1 P）是一种脑内富集的RNA结合蛋白。它的功能丧失是不能容忍的， 老鼠和人类都是。大规模的基因组关联研究和最近的基因网络分析， 将FXR 1确定为精神疾病的高置信风险基因。FXR 1 P具有独特的蛋白质结构域， 其作用机制与其X连锁同源物脆性X智力低下蛋白不同。由于 FXR 1 P基因敲除小鼠的新生儿死亡率FXR 1 P缺陷对脑发育和出生后的影响 大脑功能还未被探索FXR 1 P广泛表达于脑内兴奋性和抑制性神经元， 哺乳动物的大脑在整个出生后的发展和成人。有限的文献和我们的初步数据 提示FXR 1 P在抑制性神经元和兴奋性神经元中可能具有不同的功能。FXR 1 P的功能 在interneurons尚未研究。复杂的神经元信息处理依赖于精确的空间 和主要兴奋性神经元的时间协调，这需要密切的相互作用， 兴奋性和抑制性中间神经元。在抑制性神经元中，快速发放，小白蛋白（PV）表达 中间神经元（PVIs）已经成为许多形式的电路活动中的关键参与者。PVI提供了 对兴奋性神经元的反馈和前馈抑制，并夹带皮层网络以驱动伽马射线 振动并控制其频率和强度。广泛的研究表明伽马振荡 对感觉处理、注意力、工作记忆和认知都很重要，这些都是在一个 一些精神疾病，包括自闭症和精神分裂症。然而，基因表达的调节 在PVIs中，受到的关注有限。我们发现FXR 1 P在成年小鼠的PVI中有表达， 皮层我们的初步数据显示，PVI特异性FXR 1 P缺失的小鼠表现出行为缺陷， 这需要前额皮质（PFC）的正常功能。有趣的是，这些行为变化并不存在于 FXR 1 P仅在前脑兴奋性神经元中缺失的小鼠。我们假设FXR 1 P调节基因 PFC中PVI的表达，以控制PVI兴奋性、突触可塑性和回路功能，以及FXR 1 P PVIs的缺乏改变了导致行为缺陷的皮层回路活动。我们将决定 PFC中PVI中的FXR 1 P缺乏导致PVI生理学和连接缺陷，损害PFC- 依赖行为和特定基因网络的变化。这项工作将最先进的技术结合在一起 在一个多学科的方法来研究如何FXR 1 P缺乏影响的功能，一个重要的类型， 的interneuron。我们的方法为评估其他潜在的重要基因提供了一个潜在的框架 在PVIs和其他遗传定义的神经元群体中，功能尚不清楚。