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

描述（由申请人提供）：脆性X综合征（FXS）是遗传性人类智力迟钝的最常见形式。对脆性X患者的大脑和该疾病的小鼠模型（Fmr1敲除）进行的神经解剖学研究显示，新皮层、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细长，并且数量增加。在健康的大脑中，树突棘包含兴奋性突触的突触后末端，这表明兴奋性传递可能在FXS大脑的受影响部位发生改变。体外研究显示突触可塑性异常（海马LTD增加，新皮层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。

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.