THE EFFECT OF INTERNEURON LOSS ON MINICOLUMN STRUCTURE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。兴奋和抑制之间的正确平衡对于大脑的基本运作至关重要，无论是初级，单峰还是异峰新皮层。研究表明，自闭症患者大脑中的微柱比对照组窄，内部结构发生了变化。(1)更具体地说，它们的微柱揭示了更少的外周神经间隙和其组成细胞之间的间距增加。周围神经间隙是抑制性局部回路投射的通道。这些GABA能纤维的缺陷可能与自闭症患者癫痫发作的发病率增加有关。不出所料，有人认为自闭症患者表现出的一些行为可能源于兴奋和抑制之间的不平衡。最近的一项研究表明，？单个基因突变可以以区域和细胞亚型特异性的方式选择性地改变皮层中间神经元的发育，缺陷导致电路组织和行为的长期变化。mi（uPAR）的目标是影响神经元间迁移的突变。与野生型（WT）同窝仔相比，前扣带和顶叶皮质区含有少50%的GABA能中间神经元。在视觉或梨状皮质中没有发现差异。小清蛋白（PV）亚型完全丢失，其他类别保持完整。已知对PV具有免疫反应性的GABA能型细胞包括篮状细胞和枝状细胞。单个基因突变导致特定GABA能中间神经元的某些群体中的主要损失的能力在与自闭症相关的遗传缺陷方面特别重要。在南卡罗来纳州自闭症项目的前100例中发现的最普遍的遗传或环境因素是染色体15 q的异常，该异常具有三个GABA受体亚基基因。此外，uPAR品系的小鼠表现出与自闭症相关的某些行为，包括癫痫发作障碍的倾向以及增加的焦虑和胆怯或隐居样行为。因此，我们试图确定是否皮质微柱，代表细胞索马和顶端树突束，是窄的uPAR小鼠比WT。其次，我们将确定GABA能中间神经元在uPAR小鼠中的分布。阳性结果表明，GABA能中间神经元的缺失可导致微柱变窄，与自闭症患者的微柱相似。uPAR小鼠中类似自闭症行为的表现，连同本研究的积极结果，可以促进其作为自闭症动物模型的使用。具体目的1：确定GABA能抑制性中间神经元的减少是否与锥体细胞阵列的变窄有关。具体目标2：确定GABA能细胞的减少是否与第V层顶端树突束之间的狭窄相关。具体目的3：确定uPAR小鼠桶皮质中GABA能细胞损失的程度。

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.