THE EFFECT OF INTERNEURON LOSS ON MINICOLUMN STRUCTURE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 兴奋和抑制之间的正确平衡是基本操作的关键 无论是初级、单峰或异峰新皮层。研究表明 自闭症患者大脑中的微柱比对照组的要窄， 改变了内部结构(1)更具体地说，他们的微柱揭示的 周围神经间隙和其组成细胞之间的间距增加。外围 神经间隙是抑制性局部回路投射的通道。一 这些GABA能纤维的缺陷可能与癫痫发作的发病率增加有关 孤独症患者中。不出所料，有人认为，一些行为 孤独症患者表现出的焦虑可能根源于兴奋和焦虑之间的不平衡。 抑制作用最近的一项研究表明，？单个基因突变可以选择性地改变 皮质中间神经元以区域和细胞亚型特异性的方式发育， 导致电路组织和行为长期变化的缺陷。MI（uPAR） 被一种影响中间神经元迁移的突变所靶向。前扣带和 顶叶皮质区含有的GABA能中间神经元比野生型少50 型（WT）同窝仔。在视觉或梨状皮质中没有发现差异。有一个 小清蛋白（PV）亚型完全丧失，其他类别保持完整。gaba能 已知对PV具有免疫反应性的型细胞包括篮状细胞和枝形细胞。的 一个单一的基因突变的能力，造成重大损失，在某些群体的具体 GABA能中间神经元在与以下相关的遗传缺陷方面尤其重要： 自闭症在前100个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， GABA受体亚单位基因。此外，uPAR株小鼠表现出一定的 与自闭症相关的行为，包括癫痫发作的倾向， 都增加了焦虑和胆怯或隐居行为。 因此，我们试图确定皮质微柱，如细胞索马所代表的， 和顶端树突束，在uPAR小鼠中比WT窄。其次，我们将 确定GABA能中间神经元在uPAR小鼠中的分布。积极的结果将 表明GABA能中间神经元的丢失可导致类似于 to that found发现in the minicolumns微型columns列of patients患者withautism自闭症.自闭症的表现， uPAR小鼠的行为，结合本研究的阳性结果， 将其作为自闭症的动物模型。 具体目的1：确定GABA能抑制性中间神经元的减少是否是 与锥体细胞排列变窄有关。 具体目标2：确定GABA能细胞的减少是否与 在第V层顶端树突束之间变窄。 具体目的3：确定uPAR中桶皮质中GABA能细胞损失的程度 老鼠.

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.