Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism

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.

Anti-brain antibodies are associated with more severe cognitive and behavioral profiles in Italian children with Autism Spectrum Disorder

“…The former bind several different cell types in the cerebral and cerebellar cortex, hippocampus, amygdala and striatum (Wills et al, 2011). Reactivity against a 52 kDa autoantibody, later more accurately identified as the 45 kDa Ab analysed here, was primarily detected in calbindin-positive Golgi interneurons located in the Purkinje cell layer of the cerebellar cortex (Wills et al, 2007, 2011).…”

“…These autoantibodies, displaying a significantly lower prevalence in population controls compared to autistic individuals (Wills et al, 2009; Goines et al, 2011), seemingly target different brain regions, including thalamus, hypothalamus, caudate nucleus, cerebral cortex, and putamen, but most consistently the cerebellum (Cabanlit et al, 2007; Wills et al, 2007, 2011). Cerebellar specific IgG autoantibodies, initially estimated approximately 52 kDa in size and directed mainly against calretinin-positive GABAergic Golgi cells, were identified by Western Blot analysis in plasma from children with ASD (Cabanlit et al, 2007; Wills et al, 2011). Histopathological and brain imaging studies have unveiled multiple abnormalities in the cerebellum of many autistic individuals, including a significant reduction in Purkinje cell number, cytoarchitectonic abnormalities and cytoplasmic inclusions in the deep cerebellar nuclei, and vermal hypoplasia (Fatemi et al, 2012).…”

The calcium-binding protein parvalbumin modulates the firing 1 properties of the reticular thalamic nucleus bursting neurons

“…Changes in burst structure are likely to affect the information transfer gated by the inhibitory feedback projections exerted by RTN neurons on the thalamic relay cells. The outcome of this alteration could affect the transthalamic corticortical connectivity (Gollo et al 2010;Paz et al 2011;Sherman and Guillery 2011;Theyel et al 2010;Villa et al 1999) such to generate an impaired processing of the information associated to psychiatric disorders (Ferrarelli et al 2010;Gogolla et al 2009;Lawrence et al 2010;Pinault 2011;Reynolds et al 2001;Wills et al 2011). …”

Autoantibodies in Neuropsychiatric Disorders

“…Later on, the same sera cohort was studied by IHC using the rostro-caudal extent of macaque brain. A specific subgroup of GABAergic interneurons located in the V1 layer was identified as the specific target [194]. Controversially, another study suggested that this staining might be unspecific because immunoreactivity was detected using serum of both healthy controls and a ASD patient with the intriguing fact that the IgG seropositive ASD patients presented more severe behavior and emotional problems compared to the IgG seronegative ones [195].…”