Abstract
Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities.
Highlights
A growing body of experimental and clinical evidence indicate that repeated infections may constitute a vulnerability factor for the development or exacerbation of neuropsychiatric disorders entailing compromised motor function[1,2]
Here we investigated whether exposure of developing mice to Group A Streptococcus (GAS) homogenates resulted in inflammatory processes in several brain areas, we extended the analysis of brain parameters to magnetic resonance spectroscopy and neurochemistry, and performed a behavioral test battery encompassing most of the parameters often associated with PANDAS
The results indicate that sera from GAS treated mice recognized some of the proteins present in the GAS homogenate
Summary
A growing body of experimental and clinical evidence indicate that repeated infections may constitute a vulnerability factor for the development or exacerbation of neuropsychiatric disorders entailing compromised motor function[1,2]. Brimberg and collaborators reported that exposure to GAS in rats resulted in behavioral manifestations reminiscent of SC, which were alleviated by the administration of haloperidol[3] Leveraging these studies, here we tested the hypothesis that repeated exposure to GAS may constitute a vulnerability factor in the onset of neurological motor disturbances[22]. To this aim, we exposed SJL mice to repeated subcutaneous injections with a GAS homogenate[20] during development (between late infancy and young adulthood), and evaluated their short- and long-term effects on the aforementioned behavioral domains. To confirm a pathophysiological link between GAS exposure and the presence of autoantibodies directed against brain targets, we performed histochemical and immunohistochemical assessment of the potential presence of inflammatory conditions linked to the experimental model examined in the current work, with particular attention to the identification of the specific types of immune-mediated responses
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