Altered ionotropic receptor maturation in the impaired auditory critical periods of Fmr1 knockout mice

Fmr1 敲除小鼠听觉关键期受损的离子型受体成熟发生改变

• 批准号: 9751243
• 负责人: Yeri Jean Song
• 金额: $ 3.22万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751243
• 关键词: AMPA Receptors; Acoustics; Age; Animal Model; Auditory; Auditory area; Cells; Communication; Comorbidity; Complex; Data; Data Analyses; Development; Disease; Electrophysiology (science); Epilepsy; Equilibrium; Exhibits; External auditory canal; FMR1; Fragile X Syndrome; Frequencies; GABA Receptor; Gene Silencing; Glutamate Receptor; Glutamates; Heritability; Hippocampus (Brain); Histologic; Immunohistochemistry; Impairment; Intellectual functioning disability; Kinetics; Knock-out; Knockout Mice; Language Delays; Language Development; Lead; Link; Long-Term Potentiation; Measures; Mediating; Mediator of activation protein; Metabotropic Glutamate Receptors; Mus; N-Methylaspartate; Neurotransmitters; Pathway interactions; Patients; Pattern; Pharmacology; Phenotype; Predisposition; Receptor Signaling; Regulation; Research; Rodent; Role; Seizures; Sensory; Sensory Process; Signal Transduction; Slice; Speech Delay; Speech Development; Suggestion; Symptoms; Synapses; Synaptic plasticity; System; Therapeutic; Time; Work; audiogenic seizure; auditory processing; autism spectrum disorder; autistic; barrel cortex; cognitive function; critical period; developmental disease; developmental plasticity; effective therapy; experience; experimental study; gamma-Aminobutyric Acid; improved; insight; interest; mouse model; neural circuit; neurotransmission; patch clamp; premature; receptor; receptor expression; receptor function; response; sensory gating; sound; transmission process; trend; voltage

PROJECT SUMMARY: Fragile X syndrome (FXS), caused by Fmr1 gene silencing, is the most common heritable form of intellectual disability and is often comorbid with autism and seizures. In both FXS and autistic patients, the auditory cortex is of particular interest because of its crucial role in auditory processing, communication, and language development, all of which are hallmark deficits in FXS and autistic patients. Interestingly, Fmr1 knockout mice, the FXS mouse model, have both impaired plasticity during the auditory cortex critical period and altered auditory processing, suggestive of dysregulated auditory circuitry that may contribute to FXS symptoms. The auditory-specific phenotypes in both FXS patients and Fmr1 knockout mice are indicative of excitatory- inhibitory (E-I) imbalance and plasticity deficits. E-I imbalance within neural circuits is thought to underlie aspects of intellectual disability, autism, and epilepsy. E-I regulation is crucial during the critical period of development, a time of experience-dependent plasticity linked to the maturation of neurotransmitter signaling systems. Perturbations during this time can have permanent effects, and several developmental disorders are linked to impaired critical periods. Changes in ionotropic glutamate and GABA receptor expression and function, the primary mediators of excitatory and inhibitory neurotransmission, are pervasive in disorders that cause altered synaptic excitability and plasticity. My data thus far indicate that Fmr1 knockouts have significant changes in GABAA and AMPA receptor subunit expression during key ages in auditory cortex development, both in patterns suggestive of an accelerated maturation of these subunits. Despite the characterized hyperexcitable responses and plasticity deficits within the auditory cortex in FXS, the role of ionotropic receptors in auditory cortex development in FXS is unknown. Therefore, a major premise of this proposal is to evaluate the hypothesis that in the auditory cortex of Fmr1 KOs there is a precocious functional maturation of ionotropic receptors that precedes ear canal opening. My proposed project will integrate histological and electrophysiological approaches to evaluate the development of the auditory cortex in an animal model of intellectual disability, autism, and seizures. Aim 1 will determine whether GABAA receptors in Fmr1 mice have an accelerated functional maturation during the auditory cortex critical period, identifying both regional and synaptic differences across development. Aim 2 will determine whether lack of Fmr1 alters the maturation of NMDAR-only silent synapse to functional AMPAR- and NMDAR-expressing synapses within the auditory thalamocortical connections to identify these receptors' contributions to plasticity. Collectively, the results of my work will determine whether altered developmental functional maturation of ionotropic glutamate and GABA receptors can contribute to E-I imbalance and impaired plasticity within the auditory cortex to elicit the auditory-related phenotypes in FXS.

项目概要： 脆性X综合征（FXS）是由Fmr 1基因沉默引起的，是智力低下最常见的遗传形式。 残疾，并经常与自闭症和癫痫发作共病。在FXS和自闭症患者中， 由于其在听觉处理、交流和语言中的关键作用， 所有这些都是FXS和自闭症患者的标志性缺陷。有趣的是，Fmr 1基因敲除小鼠， FXS小鼠模型在听觉皮层关键期的可塑性受损， 听觉处理，提示可能导致FXS症状的听觉回路失调。的 FXS患者和Fmr 1基因敲除小鼠中的神经特异性表型表明， 抑制（E-I）失衡和可塑性缺陷。神经回路中的E-I不平衡被认为是 智力残疾、自闭症和癫痫的各个方面。E-I监管在关键时期至关重要， 发育，与神经递质信号成熟相关的经验依赖性可塑性的时间 系统.在这段时间内的干扰可能会产生永久性的影响，一些发育障碍是 与受损的关键时期有关。离子型谷氨酸和GABA受体表达的变化， 功能，兴奋性和抑制性神经传递的主要介质，在 导致突触兴奋性和可塑性改变到目前为止，我的数据表明，Fmr 1敲除具有显著的 GABAA和AMPA受体亚单位表达在听觉皮层发育关键年龄的变化， 这两种模式都暗示了这些亚基的加速成熟。尽管具有特征 FXS中听觉皮层内的超兴奋反应和可塑性缺陷，离子型的作用 FXS中听觉皮层发育中的受体是未知的。因此，这项建议的一个大前提是， 评估在Fmr 1科斯的听觉皮层中存在早熟功能的假设 在耳道开放之前离子型受体的成熟。我提议的项目将整合 组织学和电生理学方法来评估听觉皮层的发育， 智力残疾、自闭症和癫痫发作的动物模型。目的1将确定GABAA受体是否在 在听觉皮层关键期，fmr 1小鼠的功能成熟加快， 发育过程中的区域和突触差异。目标2将确定缺乏Fmr 1是否会改变 NMDAR沉默突触成熟为功能性AMPAR和NMDAR表达突触 听觉丘脑皮层连接，以确定这些受体对可塑性的贡献。统称 我的工作结果将确定是否改变了离子型谷氨酸的发育功能成熟 和GABA受体可以导致E-I失衡和听觉皮层内的可塑性受损， FXS中的神经相关表型。