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. 2008 Aug;22(6):806-16.
doi: 10.1016/j.bbi.2007.12.007. Epub 2008 Feb 8.

Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism

Loren A Martin  1 , Paul Ashwood, Daniel Braunschweig, Maricel Cabanlit, Judy Van de Water, David G Amaral
Affiliations

Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism

Loren A Martin et al. Brain Behav Immun. 2008 Aug.

Abstract

Autism together with Asperger syndrome and pervasive developmental disorder not otherwise specified form a spectrum of conditions (autism spectrum disorders or ASD) that is characterized by disturbances in social behavior, impaired communication and the presence of stereotyped behaviors or circumscribed interests. Recent estimates indicate a prevalence of ASD of 1 per 150 (Kuehn, 2007). The cause(s) of most cases of ASD are unknown but there is an emerging consensus that ASD have multiple etiologies. One proposed cause of ASD is exposure of the fetal brain to maternal autoantibodies during pregnancy [Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., 2003. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533-537]. To provide evidence for this hypothesis, four rhesus monkeys were exposed prenatally to human IgG collected from mothers of multiple children diagnosed with ASD. Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Monkeys were observed in a variety of behavioral paradigms involving unique social situations. Behaviors were scored by trained observers and overall activity was monitored with actimeters. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Treatment with IgG purified from mothers of typically developing children did not induce stereotypical or hyperactive behaviors. These findings support the potential for an autoimmune etiology in a subgroup of patients with neurodevelopmental disorders. This research raises the prospect of prenatal evaluation for neurodevelopmental risk factors and the potential for preventative therapeutics.

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Figures

Fig. 1
Fig. 1
Western blot demonstrating reactivity of maternal serum against both human (HU) and monkey (MO) fetal brain proteins. Depicted are two representative samples from the mothers of multiple children with autism (AU) demonstrating the typical patterns of reactivity noted in the samples used for the IV injection of maternal IgG. Note the reactivity in the first AU sample to a band at approximately 60 kDa (left arrow), while the second AU sample reacts to the 60 kDa band as well as a band at 73 kDa (right arrow). Plasma from a representative mother of two typically developing children (TD) lacks a response to either of these two bands. Note that the patterns of reactivity for the human and monkey brain blots are quite similar.
Fig. 2
Fig. 2
Mean episodes of pacing behavior observed during the mother preference task in control monkeys (both untreated controls and animals treated with IgG from mothers of typically developing children) compared to MAC IgG treated monkeys. The MAC IgG treated monkeys demonstrated significantly more pacing episodes than controls (U = 6.00, p = .024). Error bars represent SEM. Diamonds here, and in Figs. 3–5 and 7–8, represent scores of individual animals in each group. In some cases, scores are so similar that symbols overlap.
Fig. 3
Fig. 3
Mean episodes of whole-body stereotypies observed in control (both untreated controls and animals treated with IgG from mothers of typically developing children) and MAC IgG treated monkeys during solo observations. The MAC IgG treated monkeys displayed significantly more episodes of whole-body stereotypies than controls (U = 5.00, p = .014). Error bars represent SEM.
Fig. 4
Fig. 4
Mean episodes of whole-body stereotypies observed in control (both untreated controls and animals treated with IgG from mothers of typically developing children) and MAC IgG treated monkeys during observations with a familiar partner. The MAC IgG treated monkeys displayed more episodes of whole-body stereotypies than control monkeys, although the results only approached significance (U = 7.00, p = .076). Data analysis of the number and duration of extended stereotypy bouts were significant during this task (frequency: U = 5.00, p = .014; Duration: U = 5.00, p = .014). Error bars represent SEM.
Fig. 5
Fig. 5
Mean episodes of whole-body stereotypies observed in control (both untreated controls and animals treated with IgG from mothers of typically developing children) and MAC IgG treated monkeys during observations with an unfamiliar partner. The MAC IgG treated monkeys displayed significantly more episodes of whole-body stereotypies than control monkeys (U = 5.50, p = .028). Error bars represent SEM.
Fig. 6
Fig. 6
Mean number of activity counts (arbitrary units) per 30 s of monitoring for control (both untreated controls and animals treated with IgG from mothers of typically developing children) and MAC IgG monkeys during day and night combined, day only, and night only, in both social housing and individual housing conditions. There were no differences in activity demonstrated during the social housing condition. When the monkeys were removed from their social cages and placed into individual housing, significantly higher activity counts were recorded for the MAC IgG treated monkeys (day and night combined: t(11) = 2.954, p = .013). Error bars represent SEM.
Fig. 7
Fig. 7
Mean episodes of whole-body stereotypies observed in control (both untreated controls and animals treated with IgG from mothers of typically developing children) and MAC IgG treated monkeys over eight 10 min observation periods occurring during solo activity monitoring. The data are shown per 5 min of observation for comparison with previous figures. The MAC IgG treated monkeys displayed significantly more episodes of whole-body stereotypies than control monkeys (U = 0.00, p = .003). Error bars represent SEM.
Fig. 8
Fig. 8
Scatterplot of the whole-body stereotypy and activity count data of the 4 MAC IgG treated monkeys collected during eight 10 min observation periods. The numbers of stereotypies do not appear to be closely related to the activity counts indicating that the stereotypic movements were largely independent of generalized activity.
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Comment in

  • Autistic children: a neuroimmune perspective.
    Dantzer R, Kelley KW. Dantzer R, et al. Brain Behav Immun. 2008 Aug;22(6):804-5. doi: 10.1016/j.bbi.2008.03.001. Epub 2008 Apr 16. Brain Behav Immun. 2008. PMID: 18420377 No abstract available.

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