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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

Cellular profiles are also shown in the subcortical white matter in sections in which plasma stained GABAergic neurons. (A) Phase-contrast photomicrograph of AU-immunoreactive, presumed microglial cells located in the white matter deep within the somatosensory cortex. (B) Similar region from a section reacted with plasma from a representative typically developing child in which no microglial labeling is observed. Calibration bar, 25 μm.
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Figure 9: Cellular profiles are also shown in the subcortical white matter in sections in which plasma stained GABAergic neurons. (A) Phase-contrast photomicrograph of AU-immunoreactive, presumed microglial cells located in the white matter deep within the somatosensory cortex. (B) Similar region from a section reacted with plasma from a representative typically developing child in which no microglial labeling is observed. Calibration bar, 25 μm.

Mentions: We did not observe any autoantibody-stained profiles within major fiber bundles such as the corpus callosum or the anterior commissure. However, in the white matter just subjacent to the neocortex, we did see reactive profiles that resembled microglial cells (Figure 9). Since we saw no evidence of astroglial staining in the cerebellum (Bergmann glial cells) or labeling of glial end-feet along the vasculature, these subcortical microglial cells appear to be the only non-neuronal cells immunoreactive with the autoantibodies. Interestingly, Butovsky et al. [39] recently demonstrated that exposure of microglia to the proinflammatory cytokine interferon-γ induced them to express both GABA and GAD67. Microglia also express GABAB receptors [40].


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)

Cellular profiles are also shown in the subcortical white matter in sections in which plasma stained GABAergic neurons. (A) Phase-contrast photomicrograph of AU-immunoreactive, presumed microglial cells located in the white matter deep within the somatosensory cortex. (B) Similar region from a section reacted with plasma from a representative typically developing child in which no microglial labeling is observed. Calibration bar, 25 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: Cellular profiles are also shown in the subcortical white matter in sections in which plasma stained GABAergic neurons. (A) Phase-contrast photomicrograph of AU-immunoreactive, presumed microglial cells located in the white matter deep within the somatosensory cortex. (B) Similar region from a section reacted with plasma from a representative typically developing child in which no microglial labeling is observed. Calibration bar, 25 μm.
Mentions: We did not observe any autoantibody-stained profiles within major fiber bundles such as the corpus callosum or the anterior commissure. However, in the white matter just subjacent to the neocortex, we did see reactive profiles that resembled microglial cells (Figure 9). Since we saw no evidence of astroglial staining in the cerebellum (Bergmann glial cells) or labeling of glial end-feet along the vasculature, these subcortical microglial cells appear to be the only non-neuronal cells immunoreactive with the autoantibodies. Interestingly, Butovsky et al. [39] recently demonstrated that exposure of microglia to the proinflammatory cytokine interferon-γ induced them to express both GABA and GAD67. Microglia also express GABAB receptors [40].

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