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Role of inhibition in shaping neocortical activity: normal vs fmr1 knockout mouse

抑制在塑造新皮质活动中的作用：正常小鼠与 fmr1 敲除小鼠

基本信息

批准号：
7581035
负责人：
Robert C Foehring
金额：
$ 7.35万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-08 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7581035
关键词：
Ablation Address Affect Animals Behavioral Brain Brain Part Cerebellum Clinical Cognition Disorders Cognitive Defect Deformity Dendritic Spines Disease Effectiveness Electrodes Electrophysiology (science)Epilepsy Equilibrium Excitatory Synapse FMR1 FMR1 Gene FMRP Fragile X Syndrome Functional disorder Hippocampus (Brain)Human Hypersensitivity In Vitro Inherited Interneurons Knockout Mice Mental Retardation Modeling Morphology Mus Neocortex Neurons Patients Probability Property Research Rodent Role Seizures Sensory Shapes Structure Symptoms Synaptic Transmission Synaptic plasticity Techniques Testing Vertebral column Vibrissae Whole-Cell Recordings awake barrel cortex base extracellular hippocampal pyramidal neuron immunocytochemistry in vivo loss of function mouse model neocortical postsynaptic receptive field research study response sensory stimulus transmission process

项目摘要

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common form of inherited human mental retardation. Neuroanatomical studies of the brains of fragile X patients and of a mouse model of the disease (Fmr1 knock-out) showed a significantly altered morphology of neurons in the neocortex, cerebellum, as well as other parts of the brain. The key anatomical finding is that dendritic spines are abnormally thin and long, as well as increased in number. In healthy brains dendritic spines contain the postsynaptic terminals of excitatory synapses, suggesting that excitatory transmission may be altered in affected parts of FXS brains. In vitro studies have shown abnormal synaptic plasticity (increased LTD in hippocampus and decreased LTD in the neocortex). The cognitive, sensory, and behavioral deficits in human fragile X strongly implicate neocortical dysfunction. Based on the FXS-associated changes in spine morphology of cortical neurons, hypersensitivity to sensory input, and increased probability of seizures, the investigators hypothesize that cortical function in FXS patients is impaired due to increased excitability of the neocortical network. It is unclear whether the primary cause of these symptoms is increased excitability of pyramidal neurons, a reduced effectiveness of inhibitory interneurons, or a combination of these. Here the investigators propose to combine in vivo and in vitro electrophysiological experiments to determine how FXS changes the function of the cortical network in awake, behaving animals and how these network changes relate to alterations in synaptic transmission or excitability in different types of cortical neurons. This project will focus particularly on the effects of FXS on inhibition. The investigators will compare normal and Fmr1 knock-out mice using the whisker-barrel cortex as a model for neocortical function. The rodent whisker barrel cortex has two major advantages: 1) its normal function has been thoroughly investigated and documented, and 2) neurons in the barrel cortex express the typical anatomical abnormalities of fragile X brains. The proposed project has two aims: Specific Aim 1 will determine the effects of fragile X syndrome on (1) the function of the awake neocortical network, and (2) intracortical inhibition using the Frm1 knock-out mouse barrel cortex as a model. The investigators will use multiple electrode extracellular recording techniques to compare spontaneous and task-related neuronal activity in the barrel cortex of awake behaving wild-type and Fmr1 null mice. They will also determine the role of inhibition in shaping size and response properties of whisker barrel receptive fields. Specific Aim 2 will determine the effects of fragile X syndrome on excitability and synaptic transmission in fast spiking interneurons. The investigators in addition will address the potential cellular underpinning for network effects in Aim 1. They will also test whether defects in Frm1 null mice are restricted to neurons with spines or also include sparsely or aspiny interneurons. Immunocytochemistry will be used to test for FMRP expression in GABAergic interneurons and whole cell recordings for changes in intrinsic excitability, excitatory drive to interneurons, and the balance of excitation/inhibition on to layer V pyramidal neurons.

描述（由申请人提供）：脆性X综合征（FXS）是遗传性人类智力低下的最常见形式。对脆性X患者和该疾病的小鼠模型（Fmr 1敲除）的大脑进行的神经解剖学研究显示，新皮质、小脑以及大脑其他部位的神经元形态发生了显著改变。关键的解剖学发现是树突棘异常地细和长，以及数量的增加。在健康的大脑中，树突棘含有兴奋性突触的突触后末端，这表明FXS大脑的受影响部分可能会改变兴奋性传递。体外研究显示突触可塑性异常（海马中LTD增加，新皮质中LTD减少）。人类脆性X染色体的认知、感觉和行为缺陷与新皮质功能障碍密切相关。基于FXS相关的皮质神经元脊柱形态学变化、对感觉输入的超敏反应和癫痫发作概率增加，研究人员假设FXS患者的皮质功能受损是由于新皮质网络的兴奋性增加。目前尚不清楚这些症状的主要原因是锥体神经元的兴奋性增加，抑制性中间神经元的有效性降低，还是这些的组合。在这里，研究人员建议结合联合收割机在体内和体外的电生理实验，以确定FXS如何改变清醒，行为动物的皮层网络的功能，以及这些网络的变化如何与突触传递或兴奋性在不同类型的皮层神经元的改变。该项目将特别关注FXS对抑制的影响。研究人员将使用须桶皮质作为新皮质功能的模型来比较正常和Fmr 1基因敲除小鼠。啮齿动物须桶皮质有两个主要优势：1）其正常功能已被彻底研究和记录，2）桶皮质中的神经元表达脆性X脑的典型解剖异常。该项目有两个目标：具体目标1将确定脆性X综合征对（1）清醒的新皮层网络功能的影响，以及（2）使用Frm 1敲除小鼠桶状皮层作为模型的皮质内抑制。研究人员将使用多电极细胞外记录技术来比较清醒行为野生型和Fmr 1基因敲除小鼠桶状皮层中的自发和任务相关神经元活动。他们还将确定抑制的作用，在塑造尺寸和响应特性的晶须桶感受野。具体目标2将确定脆性X综合征的兴奋性和突触传递的影响，在快速尖峰中间神经元。此外，研究人员还将在目标1中讨论网络效应的潜在细胞基础。他们还将测试Frm 1基因缺失小鼠的缺陷是否仅限于有棘的神经元，或者还包括稀疏或多刺的中间神经元。免疫细胞化学将用于检测GABA能中间神经元中的FMRP表达，并用于全细胞记录内在兴奋性、中间神经元的兴奋性驱动以及V层锥体神经元的兴奋/抑制平衡的变化。