THE EFFECT OF INTERNEURON LOSS ON MINICOLUMN STRUCTURE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。兴奋和抑制之间的正确平衡对大脑的基本运作至关重要，无论是初级、单峰还是异峰的新皮层。研究表明，自闭症患者大脑中的小柱比对照组窄，内部结构也发生了改变。(1)更具体地说，它们的小柱显示出更少的周围神经细胞空间和组成细胞之间的间距增加。除其他外，外周神经空间是抑制局部电路投射的通道。这些gaba能纤维的缺陷可能与自闭症患者癫痫发作的患病率增加有关。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？单个基因突变可以选择性地以特定区域和细胞亚型的方式改变皮层中间神经元的发育，缺陷导致回路组织和行为的长期变化。mi（uPAR）以影响神经元间迁移的突变为目标。前扣带和顶叶皮质区含有的gaba能中间神经元比野生型（WT）幼崽少50%。视觉和梨状皮质没有发现差异。小白蛋白（PV）亚型完全消失，其他类别保持完整。已知对PV有免疫反应的gaba能型细胞包括篮状细胞和枝形细胞。单个基因突变在某些特定gaba能中间神经元群体中造成重大损失的能力在与自闭症相关的遗传缺陷方面尤为重要。在南卡罗莱纳自闭症项目的前100个病例中，最普遍的遗传或环境因素是15q染色体异常，该染色体有三个GABA受体亚基基因。此外，uPAR菌株的小鼠表现出与自闭症相关的某些行为，包括癫痫发作的倾向，以及焦虑和胆怯或隐居行为的增加。因此，我们试图确定以细胞体和顶端树突束为代表的皮质小柱在uPAR小鼠中是否比WT更窄。其次，我们将确定uPAR小鼠中gaba能中间神经元的分布。阳性结果表明，gaba能中间神经元的缺失会导致小柱变窄，类似于自闭症患者的小柱变窄。在uPAR小鼠中自闭症样行为的表现，结合本研究的积极结果，可以促进其作为自闭症动物模型的使用。特异性目的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。特异性目的2：确定gaba能细胞的减少是否与V层顶端树突束之间的狭窄有关。特异性目的3：确定uPAR小鼠脑桶皮质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.