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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 the dorsal portion of the amygdala of the macaque monkey. (A) Nissl-stained section of the dorsolateral portion of the amygdala. Much of the field is taken up by the central nucleus that can be divided into lateral (CEl) and medial (CEm)divisions. The basal nucleus (B) is located just ventral to the central nucleus. The substantia innominata (SI) is located just dorsal to the central nucleus. (B) Immunohistochemical staining of the amygdala using plasma from a representative child with autism. Labeled neurons are observed throughout all nuclei of the amygdala. In the central nucleus, the lateral nucleus has relatively few labeled neurons, whereas the density, size and dendritic staining of cells is much more prominent in the medial portion of the central nucleus. Calibration bar, 250 μm.
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Figure 7: Photomicrographs of the dorsal portion of the amygdala of the macaque monkey. (A) Nissl-stained section of the dorsolateral portion of the amygdala. Much of the field is taken up by the central nucleus that can be divided into lateral (CEl) and medial (CEm)divisions. The basal nucleus (B) is located just ventral to the central nucleus. The substantia innominata (SI) is located just dorsal to the central nucleus. (B) Immunohistochemical staining of the amygdala using plasma from a representative child with autism. Labeled neurons are observed throughout all nuclei of the amygdala. In the central nucleus, the lateral nucleus has relatively few labeled neurons, whereas the density, size and dendritic staining of cells is much more prominent in the medial portion of the central nucleus. Calibration bar, 250 μm.

Mentions: Autoantibody-labeled cells were distributed throughout all nuclei of the amygdala (Figure 7). Both the distribution and the appearance of the labeled neurons resembled GABAergic neurons based on our previous evaluation of GABA, GAD and parvalbumin labeling [34,37]. We have illustrated the distribution of autoantibody-labeled cells in and around the central nucleus of the amygdala (Figure 7). We had previously found that GABAergic neurons in the central nucleus do not stain well using antibodies directed against GABA [34]. However, in situ hybridization with probes to GAD65 or GAD67 demonstrated a very high density of GABAergic neurons spread more or less uniformly across the lateral and medial divisions of the nucleus. Interestingly, autoantibody labeling consistently demonstrated a high density of immunoreactive neurons with prominent dendritic staining located in the medial division of the nucleus. The lateral division, in contrast, demonstrated rather meager neuronal labeling reminiscent of the striatal labeling (see 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 the dorsal portion of the amygdala of the macaque monkey. (A) Nissl-stained section of the dorsolateral portion of the amygdala. Much of the field is taken up by the central nucleus that can be divided into lateral (CEl) and medial (CEm)divisions. The basal nucleus (B) is located just ventral to the central nucleus. The substantia innominata (SI) is located just dorsal to the central nucleus. (B) Immunohistochemical staining of the amygdala using plasma from a representative child with autism. Labeled neurons are observed throughout all nuclei of the amygdala. In the central nucleus, the lateral nucleus has relatively few labeled neurons, whereas the density, size and dendritic staining of cells is much more prominent in the medial portion of the central nucleus. Calibration bar, 250 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Photomicrographs of the dorsal portion of the amygdala of the macaque monkey. (A) Nissl-stained section of the dorsolateral portion of the amygdala. Much of the field is taken up by the central nucleus that can be divided into lateral (CEl) and medial (CEm)divisions. The basal nucleus (B) is located just ventral to the central nucleus. The substantia innominata (SI) is located just dorsal to the central nucleus. (B) Immunohistochemical staining of the amygdala using plasma from a representative child with autism. Labeled neurons are observed throughout all nuclei of the amygdala. In the central nucleus, the lateral nucleus has relatively few labeled neurons, whereas the density, size and dendritic staining of cells is much more prominent in the medial portion of the central nucleus. Calibration bar, 250 μm.
Mentions: Autoantibody-labeled cells were distributed throughout all nuclei of the amygdala (Figure 7). Both the distribution and the appearance of the labeled neurons resembled GABAergic neurons based on our previous evaluation of GABA, GAD and parvalbumin labeling [34,37]. We have illustrated the distribution of autoantibody-labeled cells in and around the central nucleus of the amygdala (Figure 7). We had previously found that GABAergic neurons in the central nucleus do not stain well using antibodies directed against GABA [34]. However, in situ hybridization with probes to GAD65 or GAD67 demonstrated a very high density of GABAergic neurons spread more or less uniformly across the lateral and medial divisions of the nucleus. Interestingly, autoantibody labeling consistently demonstrated a high density of immunoreactive neurons with prominent dendritic staining located in the medial division of the nucleus. The lateral division, in contrast, demonstrated rather meager neuronal labeling reminiscent of the striatal labeling (see 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