Neural coordination and discoordination in Fmr1 null mice

摘要 FMR1基因全突变导致脆性X智力低下蛋白(FMRP)和脆性X 以具有破坏性认知后果和特征的智力残疾为特征的综合征(FXS) 患有自闭症。Fmr1基因敲除(KO)小鼠FXS基因缺陷研究发现FMRP缺失 失调突触的翻译，导致突触功能障碍，例如过度突触 1组mGluR刺激后抑郁。不幸的是，尽管对 FMR1改变的分子后果，分子变化如何导致临床、认知 其表现尚不清楚。 我们考虑系统层面的分析，并使用海马体作为认知系统的模型。我们建议 Fmr1KO小鼠认知障碍是由于携带信息的海马主细胞不能表达所致 由于突触传递的失调，Spike训练以代表不同的信息流。 结果，当FXS模型小鼠被挑战产生独特的 在与先前学习到的信息不一致的情况下的神经表征。 局部海马区细胞棘波序列时间协调性分析的初步结果 场电位(LFP)、联合动作电位和LFP(尖峰-场)协调提供了大量 支持这项工作的中心“兴奋-抑制不协调”假说的证据。假说 认为FXS中的认知缺陷是由于学习失调导致突触改变而产生的 网络功能导致兴奋性神经元和抑制性神经元网络内的不协调放电。 我们通过比较FXS模型和对照组小鼠在各种记忆辨别任务中的表现来检验这一假说。 我们将研究在所有细胞中基因都发生突变的传统Fmr1KO小鼠，以及在 突变仅限于兴奋性(Fmr1 Koe)或抑制性(Fmr1 Koi)神经元，以了解 一个细胞类别的功能障碍足以导致认知功能障碍。我们还将测量内存如何 训练通过记录海马区的诱发电位改变海马区内的突触功能 自由行为小鼠背侧海马体树突触室。最后，我们会 研究记忆相关的Fmr1区细胞集合放电是如何被 LFP中的振荡来自于不同树突隔间的输入，并因果地测试 通过对输入进行化学操作，异常会导致记忆辨别能力受损。 这些研究评估了一种新的、电路驱动的神经调节治疗概念，用于减少认知能力 FXS的残疾，也许还有其他障碍。

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.