Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating and immune activation in rostral diencephalon

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.

Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies

“…These observations are in line with pharmacological evidence indicating that several serotonergic agonists may constitute an effective treatment for the GABHS-dependent psychiatric symptoms (Swedo and Grant, 2005 ; Murphy et al, 2010 ). Additionally, these results parallel our study in which we showed that active streptococcal immunization throughout development may alter serotonergic transmission in the adult brain (Macrì et al, 2015 ). In the same study, Lotan et al ( 2014 ) addressed whether the antibodies produced in response to GABHS were sufficient to induce an abnormal phenotype.…”

“…Other experimental studies, using a different approach based on active immunization, reported that streptococcal infections may trigger, in the presence of a vulnerable BBB, basal ganglia dysfunctions (Swerdlow and Sutherland, 2005 ). These studies show that streptococcus exposure may favor the onset of behavioral disturbances and neurochemical alterations, thereby providing additional information regarding PANDAS etiology (Hoffman et al, 2004 ; Yaddanapudi et al, 2010 ; Brimberg et al, 2012 ; Macrì et al, 2015 ). These results may support the hypothesis that antibodies produced in response to streptococcus infections may bind, in a context of BBB permeability, brain targets at the level of basal ganglia, causing the onset of behavioral and motor disturbances and neurochemical alterations (Martino et al, 2009 ).…”

“…Recently, we repeatedly exposed developing male SJL/J mice to a GABHS homogenate, showing that a single exposure to streptococcus is not sufficient to trigger behavioral abnormalities related to PANDAS (Macrì et al, 2015 ). In particular, we exposed mice to a primary immunization (GABHS homogenate emulsified in CFA), followed by three boosts (GABHS homogenate emulsified in incomplete Freund's adjuvant).…”

“…Animal models may allow testing different hypotheses regarding the role exerted by variable factors in the onset and course of a given disease, and to design innovative therapeutic approaches (Rickard, 2004 ; van der Staay, 2006 ; van der Staay et al, 2009 ). Within this framework, several aspects of TS (symptomatology, genetic predisposition and environmental risk factors) have been translated into preclinical animal models (Hallett et al, 2000 ; Yaddanapudi et al, 2010 ; Brimberg et al, 2012 ; Macrì et al, 2015 ; see Macrì et al, 2013 for a detailed review).…”

Sydenham's Chorea; Clinical and Magnetic Resonance Imaging Findings, a Retrospective Observational Study in Children

“…Animal studies using mouse models have demonstrated that serum immunoglobulin G (IgG) is principally deposited inside the hippocampus, deep cerebellar nuclei, or rostral diencephalon, and that very low levels of IgG are present in the basal ganglia. [10][11][12] However, significant IgG deposition has been observed in the prefrontal cortex and basal ganglia in a rat model. 13,14 This bears a closer similarity to the human disease in which neuroimaging studies have shown powerful evidence of neuroinflammation in the basal ganglia and thalamus.…”