Abstract
BackgroundAutism 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.MethodsWe 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.ResultsIn 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.ConclusionsThese 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.
Highlights
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
We have demonstrated that the plasma from children with autism spectrum disorder (ASD) contains antibodies that are reactive to neurons throughout the brain that are invariably GABAergic interneurons
Parvalbumin is associated with chandelier and large basket cells; calretinin is associated with bipolar, double-bouquet and Cajal-Retzius cells; and calbindin is associated with double-bouquet, neurogliaform, Martinotti and, in rare cases, Cajal-Retzius cells
Summary
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. Autism is a lifelong neurodevelopmental disorder that is diagnosed in early childhood and is characterized by a core deficit in social interaction with impairments in communication, stereotypical movements and restricted behaviors [1]. Converging evidence over the past 40 years indicates that immune dysfunction may be an important factor contributing to the development of a subset of cases of autism [2,3,4]. Several studies have shown peripheral immune abnormalities in patients with autism [5,6,7]. The possibility has been raised that some forms of autism may be due to an autoimmune process [10]. The potential for an autoimmune etiology with respect to psychiatric disorders, including the pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, remains intriguing but controversial [14]
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