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

项目总结： 脆性X综合征(FXS)是由Fmr1基因沉默引起的，是最常见的可遗传形式的智力 残疾，往往与自闭症和癫痫并存。在FXS和自闭症患者中，听觉皮质 因为它在听觉处理、交流和语言中起着至关重要的作用，所以特别值得关注 发展，所有这些都是FXS和自闭症患者的标志性缺陷。有趣的是，Fmr1基因敲除小鼠， FXS小鼠模型在听皮质关键期可塑性受损和改变 听觉处理，提示听觉回路失调，可能导致FXS症状。这个 FXS患者和Fmr1基因敲除小鼠的听觉特异性表型都表明兴奋性- 抑制性(E-I)失衡和可塑性缺陷。神经回路中的E-I失衡被认为是基础 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，依赖经验的可塑性与神经递质信号成熟有关的时间 系统。在这段时间内的干扰可能会产生永久性的影响，几种发育障碍是 与受损的关键时期有关。离子型谷氨酸和GABA受体表达的变化及 功能是兴奋性和抑制性神经传递的主要媒介，在以下疾病中普遍存在 导致突触兴奋性和可塑性改变。到目前为止，我的数据表明Fmr1基因敲除具有显著的 GABAA和AMPA受体亚单位在听皮质发育关键年龄期间的表达变化， 两者的模式都暗示着这些亚基的加速成熟。尽管其特点是 FXS中听皮层内的过度兴奋反应和可塑性缺陷，离子亲和性的作用 FXS听觉皮质发育中的受体尚不清楚。因此，这一建议的一个大前提是 对Fmr1KO的听觉皮质存在早熟功能的假设进行评估 在耳道打开之前，电离子感受器的成熟。我提议的项目将整合 用组织学和电生理学方法评价听皮质发育 智力残疾、自闭症和癫痫的动物模型。AIM 1将确定GABAA受体是否在 FMR1小鼠在听皮质关键期的功能成熟加速，两者都被识别出来 不同发育阶段的区域和突触差异。目标2将确定Fmr1的缺失是否会改变 脑内仅表达NMDAR的沉默突触与表达AMPAR和NMDAR的功能性突触的成熟 听觉丘脑皮质连接，以确定这些受体对可塑性的贡献。总体而言， 我的工作结果将决定离子型谷氨酸的发育功能成熟是否发生变化 而GABA受体可以促进E-I失衡和听觉皮质内的可塑性受损 FXS的听觉相关表型。

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.