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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 兴奋和抑制之间的正确平衡是基本运作的关键 大脑的新皮质，无论是初级、单峰还是异峰新皮质。研究表明 自闭症患者大脑中的微柱比对照组更窄， 改变了内部配置。 (1) 更具体地说，它们的迷你柱揭示的信息较少 周围神经纤维间隙及其组成细胞之间的间距增加。周边 神经纤维网空间是抑制性局部回路投射等的通道。一个 这些 GABA 能纤维的缺陷可能与癫痫发作率增加有关 在自闭症患者中。毫不奇怪，有人认为某些行为 自闭症患者表现出的行为可能源于兴奋和兴奋之间的不平衡。 抑制。最近的一项研究表明，单个基因突变可以选择性地改变 以区域和细胞亚型特异性方式发育皮质中间神经元， 缺陷导致电路组织和行为的长期变化。 mi(uPAR) 被靶向影响中间神经元迁移的突变。前扣带回和 与野生型相比，顶皮质区域含有的 GABA 能中间神经元减少了 50% 型（WT）同窝仔猪。视觉皮层或梨状皮层没有发现差异。有一个 小清蛋白 (PV) 亚型完全丧失，而其他类别保持完整。 GABA能 已知对PV有免疫反应的类型细胞包括篮子细胞和吊灯细胞。这 单个基因突变能够导致某些特定群体的重大损失 GABA能中间神经元对于与以下相关的遗传缺陷尤其重要 自闭症。前 100 个病例中发现的最普遍的遗传或环境因素 南卡罗来纳州自闭症项目中的一个异常是 15q 染色体，有 3 个异常。 GABA 受体亚基基因。此外，uPAR 品系的小鼠表现出某些 与自闭症相关的行为，包括癫痫发作的倾向和 都会增加焦虑和胆怯或隐士般的行为。 因此，我们试图确定以细胞体为代表的皮质微柱是否 uPAR 小鼠的顶端树突束比 WT 更窄。其次，我们将 确定 uPAR 小鼠中 GABA 能中间神经元的分布。积极的结果将 表明 GABA 能中间神经元的丢失会导致类似的微柱变窄 在自闭症患者的迷你柱中发现的。自闭症的表现如 uPAR 小鼠的行为与本研究的积极结果相结合，可以 推广其作为自闭症动物模型的用途。 具体目标 1：确定 GABA 能抑制性中间神经元的减少是否与 与锥体细胞阵列变窄有关。 具体目标 2：确定 GABA 能细胞的减少是否与 V 层顶端树突束之间变窄。 具体目标 3：确定 uPAR 桶状皮层 GABA 能细胞损失的程度 老鼠。