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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

Photomicrographs of coronal sections through the posterior cingulate cortex of the macaque monkey. This level includes areas 29, 30 and 23. (A) Nissl-stained section showing the laminar pattern of posterior cingulate cortex located just dorsal to the corpus callosum (cc). The layers of cortical area 23 are marked I to VI. (B) Immunostaining with plasma from a representative child with autism. As in the primary visual cortex, the most numerous labeled neurons are located in the superficial layers (I to III), although immunopositive neurons are located throughout all layers. This pattern was recapitulated in all cortical areas. Labeled cells were not observed in the cc, although apparent positive cells were observed in the subcortical white matter. Calibration bar, 250 μm.
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Figure 5: Photomicrographs of coronal sections through the posterior cingulate cortex of the macaque monkey. This level includes areas 29, 30 and 23. (A) Nissl-stained section showing the laminar pattern of posterior cingulate cortex located just dorsal to the corpus callosum (cc). The layers of cortical area 23 are marked I to VI. (B) Immunostaining with plasma from a representative child with autism. As in the primary visual cortex, the most numerous labeled neurons are located in the superficial layers (I to III), although immunopositive neurons are located throughout all layers. This pattern was recapitulated in all cortical areas. Labeled cells were not observed in the cc, although apparent positive cells were observed in the subcortical white matter. Calibration bar, 250 μm.

Mentions: We have previously provided a detailed cytoarchitectonic analysis of the posterior and retrosplenial regions of the cingulate cortex [38]. Figure 5 shows a coronal section through this region that includes areas 29, 30 and 23. As in area V1, autoantibody-reactive cells are distributed throughout all layers of these cortical regions, with a slight predominance in superficial layers I to III. The white matter deep within these cortical areas (Figure 5B) has a mottled appearance. This is due to the labeling of a population of glial cells by the plasma. We describe these cells below.


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)

Photomicrographs of coronal sections through the posterior cingulate cortex of the macaque monkey. This level includes areas 29, 30 and 23. (A) Nissl-stained section showing the laminar pattern of posterior cingulate cortex located just dorsal to the corpus callosum (cc). The layers of cortical area 23 are marked I to VI. (B) Immunostaining with plasma from a representative child with autism. As in the primary visual cortex, the most numerous labeled neurons are located in the superficial layers (I to III), although immunopositive neurons are located throughout all layers. This pattern was recapitulated in all cortical areas. Labeled cells were not observed in the cc, although apparent positive cells were observed in the subcortical white matter. Calibration bar, 250 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Photomicrographs of coronal sections through the posterior cingulate cortex of the macaque monkey. This level includes areas 29, 30 and 23. (A) Nissl-stained section showing the laminar pattern of posterior cingulate cortex located just dorsal to the corpus callosum (cc). The layers of cortical area 23 are marked I to VI. (B) Immunostaining with plasma from a representative child with autism. As in the primary visual cortex, the most numerous labeled neurons are located in the superficial layers (I to III), although immunopositive neurons are located throughout all layers. This pattern was recapitulated in all cortical areas. Labeled cells were not observed in the cc, although apparent positive cells were observed in the subcortical white matter. Calibration bar, 250 μm.
Mentions: We have previously provided a detailed cytoarchitectonic analysis of the posterior and retrosplenial regions of the cingulate cortex [38]. Figure 5 shows a coronal section through this region that includes areas 29, 30 and 23. As in area V1, autoantibody-reactive cells are distributed throughout all layers of these cortical regions, with a slight predominance in superficial layers I to III. The white matter deep within these cortical areas (Figure 5B) has a mottled appearance. This is due to the labeling of a population of glial cells by the plasma. We describe these cells below.

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