Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510 GBSF, Davis, CA 95616, USA.
NIEHS Center for Children's Environmental Health, University of California, Davis, Davis, CA 95616, USA.
Mol Autism. 2011 Apr 26;2:5. doi: 10.1186/2040-2392-2-5.
Autism is a neurodevelopmental disorder characterized by impairments in social interaction and deficits in verbal and nonverbal communication, together with the presence of repetitive behaviors or a limited repertoire of activities and interests. The causes of autism are currently unclear. In a previous study, we determined that 21% of children with autism have plasma autoantibodies that are immunoreactive with a population of neurons in the cerebellum that appear to be Golgi cells, which are GABAergic interneurons.
We have extended this analysis by examining plasma immunoreactivity in the remainder of the brain. To determine cell specificity, double-labeling studies that included one of the calcium-binding proteins that are commonly colocalized in GABAergic neurons (calbindin, parvalbumin or calretinin) were also carried out to determine which GABAergic neurons are immunoreactive. Coronal sections through the rostrocaudal extent of the macaque monkey brain were reacted with plasma from each of seven individuals with autism who had previously demonstrated positive Golgi cell staining, as well as six negative controls. In addition, brain sections from adult male mice were similarly examined.
In each case, specific staining was observed for neurons that had the morphological appearance of interneurons. By double-labeling sections with plasma and with antibodies directed against γ-aminobutyric acid (GABA), we determined that all autoantibody-positive neurons were GABAergic. However, not all GABAergic neurons were autoantibody-positive. Calbindin was colabeled in several of the autoantibody-labeled cells, while parvalbumin colabeling was less frequently observed. Autoantibody-positive cells rarely expressed calretinin. Sections from the mouse brain processed similarly to the primate sections also demonstrated immunoreactivity to interneurons distributed throughout the neocortex and many subcortical regions. Some cell populations stained in the primate (such as the Golgi neurons in the cerebellum) were not as robustly immunoreactive in the mouse brain.
These results suggest that the earlier report of autoantibody immunoreactivity to specific cells in the cerebellum extend to other regions of the brain. Further, these findings confirm the autoantibody-targeted cells to be a subpopulation of GABAergic interneurons. The potential impact of these autoantibodies on GABAergic disruption with respect to the etiology of autism is discussed herein.
自闭症是一种神经发育障碍，其特征是社交互动受损，言语和非言语交流能力缺陷，以及重复行为或活动和兴趣范围有限。自闭症的病因目前尚不清楚。在之前的一项研究中，我们发现 21%的自闭症儿童的血浆中有自身抗体，这些自身抗体与小脑内的一群神经元反应，这些神经元似乎是高尔基细胞，是 GABA 能中间神经元。
我们通过检查大脑其余部分的血浆免疫反应，扩展了这项分析。为了确定细胞特异性，还进行了双标记研究，其中包括在 GABA 能神经元中常见的钙结合蛋白之一（钙结合蛋白、副钙蛋白或钙视网膜蛋白），以确定哪些 GABA 能神经元是免疫反应性的。用来自先前显示高尔基细胞染色阳性的 7 名自闭症患者中的每一位的血浆以及 6 名阴性对照物反应猴脑的冠状切片，通过从嘴到尾的范围。此外，还对成年雄性小鼠的脑切片进行了类似的检查。
在每种情况下，都观察到具有中间神经元形态外观的神经元的特异性染色。通过用血浆和针对 γ-氨基丁酸（GABA）的抗体对切片进行双重标记，我们确定所有自身抗体阳性神经元都是 GABA 能的。然而，并非所有 GABA 能神经元都是自身抗体阳性的。钙结合蛋白在一些自身抗体标记的细胞中被共标记，而副钙蛋白共标记则较少见。自身抗体阳性细胞很少表达钙视网膜蛋白。用与处理灵长类切片类似的方法处理的小鼠脑切片也显示出分布在新皮质和许多皮质下区域的中间神经元的免疫反应性。在灵长类动物中染色的一些细胞群（如小脑中的高尔基神经元）在小鼠脑中的免疫反应性并不那么强烈。
这些结果表明，早期报告的小脑内特定细胞的自身抗体免疫反应性延伸到大脑的其他区域。此外，这些发现证实了自身抗体靶向细胞是 GABA 能中间神经元的一个亚群。本文讨论了这些自身抗体对自闭症病因的 GABA 能破坏的潜在影响。
