THE EFFECT OF INTERNEURON LOSS ON MINICOLUMN STRUCTURE

中间神经元损失对微柱结构的影响

• 批准号: 7720697
• 负责人: Ratnam Sathiagana Seelan
• 金额: $ 6.44万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720697
• 关键词: 15q; Affect; Animal Model; Anterior; Anxiety; Apical; Area; Autistic Disorder; Behavior; Brain; Cells; Chromosome abnormality; Class; Computer Retrieval of Information on Scientific Projects Database; Defect; Dendrites; Development; Environmental Risk Factor; Epilepsy; Equilibrium; Exhibits; Fiber; Funding; GABA Receptor; Gene Mutation; Genes; Genetic; Grant; Institution; Interneurons; Mus; Mutation; Neocortex; Neuropil; Operative Surgical Procedures; Parietal; Parvalbumins; Patients; Peripheral; Plant Roots; Population; Prevalence; Pyramidal Cells; Research; Research Personnel; Resources; Seizures; Source; South Carolina; Structure; Timidity; United States National Institutes of Health; Visual; Wild Type Mouse; barrel cortex; cell type; migration; neuronal cell body; piriform cortex

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The correct balance between excitation and inhibition is pivotal to the fundamental operation of the brain, whether primary, unimodal or heteromodal neocortex. Studies have suggested that minicolumns in the brains of patients with autism are narrower than those of controls, with an altered internal configuration. (1) More specifically, their minicolumns reveal less peripheral neuropil space and increased spacing among their constituent cells. The peripheral neuropil space is the conduit for, among other things, inhibitory local circuit projections. A defect in these GABAergic fibers may correlate with the increased prevalence of seizures among autistic patients. Unsurprisingly, it has been argued that some of the behavior exhibited by autistic patients may be rooted in an imbalance between excitation and inhibition. A recent study shows that ?a single gene mutation can selectively alter the development of cortical interneurons in a region-and cell subtype-specific manner, with deficits leading to long-lasting changes in circuit organization and behavior.? The mi(uPAR) were targeted with a mutation that affects interneuron migration. Anterior cingulate and parietal cortical areas contained 50 % fewer GABAergic interneurons compared with Wild Type (WT) littermates. No differences were found in visual or piriform cortex. There was a complete loss of parvalbumin (PV) subtypes, with other classes remaining intact. GABAergic type cells known to be immunoreactive for PV include the basket and chandelier cells. The ability of a single gene mutation to cause a major loss in certain populations of specific GABAergic interneurons is especially significant in regards to genetic defects related to autism. The most prevalent genetic or environmental factor found among the first 100 cases in the South Carolina autism project is an abnormality of chromosome 15q that has three GABA receptor subunit genes. Furthermore, mice of the uPAR strain demonstrated certain behaviors associated with autism which included a propensity for seizure disorders and both increased anxiety and timidity or recluse-like behavior. Thus, we seek to determine whether the cortical minicolumn, as represented by cell soma and apical dendrite bundles, is narrower in the uPAR mouse than the WT. Secondly, we will identify the distribution of GABAergic interneurons in the uPAR mice. Positive results would show that the loss of GABAergic interneurons can cause a narrowing of minicolumns similar to that found in the minicolumns of patients withautism. The manifestations of autistic like behavior in the uPAR mouse, in conjunction with positive results from this study, could promote its use as an animal model for autism. Specific Aim 1: To determine whether a reduction in GABAergic inhibitory interneurons is associated with the narrowing of pyramidal cell arrays. Specific Aim 2: To determine whether a reduction in GABAergic cells is associated with a narrowing between layer V apical dendrite bundles. Specific Aim 3: To determine the extent of GABAergic cell loss in barrel cortex in the uPAR mouse.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 激发和抑制之间的正确平衡对于基本操作至关重要 大脑的主要，单峰或异态新皮层。研究表明 自闭症患者的大脑中的微小分子比对照组狭窄， 内部配置更改。 （1）更具体地说，他们的微型典型表现较少 周围神经胶体空间并增加其组成细胞之间的间隔。外围 Neuropil空间是抑制性局部电路预测的管道。一个 这些GABA能纤维中的缺陷可能与癫痫发作的患病率增加有关 在自闭症患者中。毫不奇怪，有人认为某些行为 自闭症患者展示的可能植根于激发和 抑制。最近的一项研究表明，单个基因突变可以选择性改变 以区域和细胞亚型特异性方式开发皮质中间神经元， 赤字导致电路组织和行为的持久变化。 Mi（UPAR） 被靶向的突变影响中间神经元的迁移。前扣带回和 与野生相比，顶叶皮质区域含有少50％ 类型（wt）同窝工人。在视觉或梨状皮层中未发现差异。有一个 白蛋白（PV）亚型的完全损失，其他类别保持完整。加巴能 已知对PV免疫反应性的类型细胞包括篮子和吊灯细胞。这 单个基因突变在某些特定种群中造成重大损失的能力 GABA能中间神经元在与与 自闭症。在前100例病例中发现的最普遍的遗传或环境因素 在南卡罗来纳州自闭症项目中，有15q染色体的异常 GABA受体亚基基因。此外，UPAR菌株的小鼠表现出一定的 与自闭症相关的行为，其中包括癫痫疾病的倾向和 增加了焦虑和胆怯或隐居状的行为。 因此，我们试图确定是否由细胞体代表的皮质微型列 和顶端树突束，在UPAR鼠标中比WT窄。其次，我们会的 确定UPAR小鼠中GABA能中间神经元的分布。积极的结果将是 表明gabaergic中间神经元的损失会导致微小级别的变窄类似 在患有自动术的患者的小班室中发现了这一点。自闭症的表现 UPAR小鼠中的行为以及这项研究的积极结果，可以 促进其用作自闭症的动物模型。 具体目的1：确定降低GABA能抑制性中间神经元是否是 与锥体细胞阵列的变窄有关。 具体目标2：确定降低GABA能细胞是否与A相关 V层顶端树突束之间的缩小。 特定目的3：确定UPAR中枪管皮层中GABA能细胞损失的程度 老鼠。