Neural coordination and discoordination in Fmr1 null mice

Fmr1 缺失小鼠的神经协调和不协调

• 批准号: 9472717
• 负责人: ANDRE ANTONIO FENTON
• 金额: $ 41.19万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9472717
• 关键词: Action Potentials; Area; Autistic Disorder; Avoidance Learning; Behavior; Behavioral; Biological; Biological Neural Networks; Brain; Budgets; Cells; Clinical; Cognitive; Cognitive deficits; Conflict (Psychology); Defect; Discrimination; Disease; Dorsal; Etiology; Evoked Potentials; FMR1; Fragile X Syndrome; Functional disorder; Genes; Genetic; Genetic Models; Hippocampus (Brain); Impaired cognition; Impairment; Intellectual functioning disability; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Measures; Memory; Memory impairment; Modeling; Modification; Molecular; Mus; Mutate; Mutation; Neurobehavioral Manifestations; Pathway interactions; Physiology; Psyche structure; Research; Role; Stream; Synapses; Synaptic Transmission; System; Testing; Therapeutic; Training; Translations; Work; cognitive disability; cognitive system; dentate gyrus; entorhinal cortex; excitatory neuron; experience; flexibility; improved; inhibitory neuron; mouse model; mutant mouse model; neural patterning; neuroregulation; novel; null mutation; operation; relating to nervous system; response; social; synaptic depression; synaptic function; theories

ABSTRACT Full mutation of the FMR1 gene causes loss of the fragile X mental retardation protein (FMRP) and fragile X syndrome (FXS) characterized by intellectual disability with devastating cognitive consequences and features of autism. Study of Fmr1 knockout (KO) mouse models of the FXS genetic defect identified that loss of FMRP dysregulates translation at synapses, leading to synaptic dysfunction, for example excessive synaptic depression in response to group 1 mGluR stimulation. Unfortunately, despite substantial knowledge of the molecular consequences of FMR1 alteration, how the molecular changes lead to the clinical, cognitive manifestations is unknown. We consider a systems level analysis and use the hippocampus as a model cognitive system. We propose that impaired cognition in Fmr1 KO mice is due to the inability of information-carrying hippocampus principal cell spike trains to represent distinct streams of information because of the dysregulation of synaptic transmission. As a result, cognitive deficits primarily manifest when FXS model mice are challenged to generate distinctive neural representations in situations that are inconsistent with the information they have previously learned. Preliminary findings from analysis of temporal coordination amongst hippocampal place cell spike trains, local field potentials (LFPs), and conjoint action potential and LFP (spike-field) coordination provide substantial evidence in support of the central “excitation-inhibition discoordination” hypothesis of this work. The hypothesis asserts that cognitive deficits in FXS arise because dysregulated learning-induced changes of synaptic network function cause discoordinated discharge within networks of excitatory and inhibitory neurons. We test the hypothesis by comparing FXS model and control mice in a variety of memory discrimination tasks. We will examine conventional Fmr1 KO mice in which the gene is mutated in all cells, as well as mice in which the mutation is restricted to excitatory (Fmr1 KOe) or inhibitory (Fmr1 KOi) neurons to learn whether dysfunction in one cell class is sufficient to cause cognitive dysfunction. We will also measure how memory training changes synaptic function within the hippocampus circuit by recording evoked potentials across the somatodendritic synaptic compartments of dorsal hippocampus in freely-behaving mice. Finally, we will investigate abnormalities in how memory-related Fmr1 place cell ensemble discharge is controlled by oscillations in the LFP that arise from inputs at distinctive dendritic compartments and causally test whether the abnormality contributes to memory discrimination impairment using chemogenetic manipulations of the inputs. These studies evaluate a novel, circuit-driven neuromodulatory therapeutic concept for reducing cognitive disability in FXS and perhaps other disorders.

摘要 FMR1基因的完全突变导致脆性X智力低下蛋白（FMRP）和脆性X染色体缺失。 一种以智力残疾为特征的综合征（FXS），具有破坏性的认知后果和特征 自闭症的症状FXS遗传缺陷的Fmr1敲除（KO）小鼠模型的研究表明，FMRP缺失 在突触处的翻译失调，导致突触功能障碍，例如过度的突触传导。 抑郁症响应于组1 mGluR刺激。不幸的是，尽管有大量的知识 FMR 1改变的分子后果，分子变化如何导致临床，认知 表现是未知的。 我们认为，系统水平的分析和使用海马作为一个模型的认知系统。我们建议 Fmr 1 KO小鼠的认知功能受损是由于海马主细胞无法携带信息 由于突触传递的失调，尖峰序列代表不同的信息流。 因此，当FXS模型小鼠受到挑战以产生独特的认知缺陷时， 在与他们先前学到的信息不一致的情况下，神经表征。 海马位置细胞锋电位序列时间协调分析的初步结果，局部 场电位（LFP），联合动作电位和LFP（尖峰场）协调提供了大量的 证据支持中央“兴奋抑制失调”假说的这项工作。的假设 声称FXS中的认知缺陷的出现是因为学习失调引起的突触变化， 网络功能引起兴奋性和抑制性神经元网络内的不协调放电。 我们通过比较FXS模型和对照小鼠在各种记忆辨别任务中的表现来验证这一假设。 我们将检查常规的Fmr1 KO小鼠，其中基因在所有细胞中突变，以及小鼠，其中 突变仅限于兴奋性（Fmr1 KOe）或抑制性（Fmr1 KOi）神经元，以了解是否 一种细胞类别的功能障碍足以引起认知功能障碍。我们还将测量记忆 训练通过记录海马回路中的诱发电位来改变海马回路中的突触功能。 自由行为小鼠背侧海马体树突突触区室。最后我们将 研究记忆相关的Fmr1定位细胞集合放电是如何被控制的异常 LFP中的振荡由独特的树枝状隔室的输入引起，并因果地测试是否 使用输入的化学遗传学操作，异常有助于记忆辨别障碍。 这些研究评估了一种新颖的，电路驱动的神经调节治疗概念，用于减少认知功能障碍。 FXS和其他疾病的残疾。