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: 10673101
• 负责人: Xinyu Zhao
• 金额: $ 42.54万
• 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/10673101
• 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; Hyperactivity; Image; Impairment; Individual; Interneurons; Knockout Mice; Learning; Link; Literature; LoxP-flanked allele; 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; Regulation; Role; Schizophrenia; Sensory; Sequence Homology; Short-Term Memory; Synapses; Synaptic plasticity; Techniques; Tertiary Protein Structure; Testing; Time; Translations; Validation; Work; autism spectrum disorder; cognitive function; cohort; excitatory neuron; experimental study; gene network; 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; rabies viral tracing; 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(FXR1P)是一种富含脑组织的RNA结合蛋白。它的功能丧失是不能容忍的 无论是老鼠还是人类。大规模的全基因组关联研究和最近的基因网络分析已经 确定FXR1是精神疾病的高自信风险基因。FXR1P具有独特的蛋白质结构域和 与其X连锁同系物脆性X智力低下蛋白不同的作用机制。由于 FXR1P缺失小鼠的新生致死率FXR1P缺乏对脑发育和出生后的影响 大脑功能在很大程度上还没有被研究。FXR1P在大脑皮层兴奋性和抑制性神经元中广泛表达。 哺乳动物的大脑在出生后的整个发育过程中和在成体中。有限的文献和我们的初步数据 提示FXR1P在抑制性神经元和兴奋性神经元中可能具有不同的功能。FXR1P的功能 在中间神经元中的作用尚未被研究过。复杂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 兴奋性和抑制性中间神经元。在抑制性神经元中，快速放电、小白蛋白(PV)表达 中间神经元(PVI)在多种形式的环路活动中扮演着重要角色。变坡点提供这两种功能 对兴奋性神经元和皮质网络的反馈和前馈抑制以驱动伽马 并控制它们的频率和强度。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，这些都会在 精神障碍的数量，包括自闭症和精神分裂症。然而，基因表达的调控 在变形器中受到的关注有限。我们发现FXR1P在成年小鼠的大多数PVI中都有表达 大脑皮层。我们的初步数据显示，带有PVI特异性FXR1P缺失的小鼠表现出行为缺陷 这需要前额叶皮质(PFC)的正常功能。有趣的是，这些行为变化在 FXR1P缺失的小鼠仅存在前脑兴奋性神经元。我们假设FXR1P调控基因 PFC中PVI的表达控制PVI的兴奋性、突触可塑性、电路功能和FXR1P PVI的缺陷改变了皮质回路的活动，导致行为障碍。我们将确定是否 PFC中PVI中FXR1P缺乏导致PVI生理和连接性缺陷，损害PFC- 依赖行为，以及特定基因网络的变化。这部作品将最先进的技术结合在一起 用多学科方法研究FXR1P缺乏如何影响一种重要类型的功能 中间神经元。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 在下丘脑室隔核和其他遗传定义的神经元群体中，功能尚不清楚。