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

Wills S, Rossi CC, Bennett J, Martinez Cerdeño V, Ashwood P, Amaral DG, Van de Water J - Mol Autism (2011)

Bottom Line: Autoantibody-positive cells rarely expressed calretinin.Some cell populations stained in the primate (such as the Golgi neurons in the cerebellum) were not as robustly immunoreactive in the mouse brain.Further, these findings confirm the autoantibody-targeted cells to be a subpopulation of GABAergic interneurons.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510 GBSF, Davis, CA 95616, USA. javandewater@ucdavis.edu.

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

No MeSH data available.


Related in: MedlinePlus

Illustrations of plasma staining of the mouse somatosensory cortex. (A) Nissl-stained section of the mouse somatosensory cortex. Layers I to VI are indicated on the right-hand side of the image. (B) Autoantibody staining of a section adjacent to the Nissl-stained section depicted in A with plasma from a representative AU subject. There are numerous immunoreactive neurons (arrows) scattered throughout all layers of the cortex. Calibration bar in B = 250 μm and applies to A as well.
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Figure 10: Illustrations of plasma staining of the mouse somatosensory cortex. (A) Nissl-stained section of the mouse somatosensory cortex. Layers I to VI are indicated on the right-hand side of the image. (B) Autoantibody staining of a section adjacent to the Nissl-stained section depicted in A with plasma from a representative AU subject. There are numerous immunoreactive neurons (arrows) scattered throughout all layers of the cortex. Calibration bar in B = 250 μm and applies to A as well.

Mentions: Given the limited supply of plasma from the participants involved in this study, we were unable to carry out an exhaustive comparison of staining in the monkey and mouse brain. However, we were able to determine that the neurons that were morphologically characterized as interneurons were also labeled in various regions throughout the mouse brain. As illustrated in Figure 10, there were populations of immunoreactive neurons scattered throughout the neocortex. Many of these cells had substantial dendritic labeling (Figure 10D), and all resembled classes of interneurons. Immunoreactive neurons were observed in the hippocampus, amygdala and other brain regions that were also noted in the monkey brain (not shown). Interestingly, while the Golgi neurons of the mouse cerebellum were lightly immunoreactive, the intensity of staining was not nearly as striking as in the monkey brain or as intensely labeled as neurons observed in other brain regions. We intend to carry out a more exhaustive species comparison in a future study.


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

Wills S, Rossi CC, Bennett J, Martinez Cerdeño V, Ashwood P, Amaral DG, Van de Water J - Mol Autism (2011)

Illustrations of plasma staining of the mouse somatosensory cortex. (A) Nissl-stained section of the mouse somatosensory cortex. Layers I to VI are indicated on the right-hand side of the image. (B) Autoantibody staining of a section adjacent to the Nissl-stained section depicted in A with plasma from a representative AU subject. There are numerous immunoreactive neurons (arrows) scattered throughout all layers of the cortex. Calibration bar in B = 250 μm and applies to A as well.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108923&req=5

Figure 10: Illustrations of plasma staining of the mouse somatosensory cortex. (A) Nissl-stained section of the mouse somatosensory cortex. Layers I to VI are indicated on the right-hand side of the image. (B) Autoantibody staining of a section adjacent to the Nissl-stained section depicted in A with plasma from a representative AU subject. There are numerous immunoreactive neurons (arrows) scattered throughout all layers of the cortex. Calibration bar in B = 250 μm and applies to A as well.
Mentions: Given the limited supply of plasma from the participants involved in this study, we were unable to carry out an exhaustive comparison of staining in the monkey and mouse brain. However, we were able to determine that the neurons that were morphologically characterized as interneurons were also labeled in various regions throughout the mouse brain. As illustrated in Figure 10, there were populations of immunoreactive neurons scattered throughout the neocortex. Many of these cells had substantial dendritic labeling (Figure 10D), and all resembled classes of interneurons. Immunoreactive neurons were observed in the hippocampus, amygdala and other brain regions that were also noted in the monkey brain (not shown). Interestingly, while the Golgi neurons of the mouse cerebellum were lightly immunoreactive, the intensity of staining was not nearly as striking as in the monkey brain or as intensely labeled as neurons observed in other brain regions. We intend to carry out a more exhaustive species comparison in a future study.

Bottom Line: Autoantibody-positive cells rarely expressed calretinin.Some cell populations stained in the primate (such as the Golgi neurons in the cerebellum) were not as robustly immunoreactive in the mouse brain.Further, these findings confirm the autoantibody-targeted cells to be a subpopulation of GABAergic interneurons.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510 GBSF, Davis, CA 95616, USA. javandewater@ucdavis.edu.

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

No MeSH data available.


Related in: MedlinePlus