Neonatal corticosterone mitigates autoimmune neuropsychiatric disorders associated with streptococcus in mice

Simone Macrì,Chiara Spinello,Roberta Creti,Geert Poelmans,Roberta Magliozzi,Roberto William Invernizzi,Giovanni Laviola,Immaculada Margarit,Veit Roessner,Erika Bartolini,Jeffrey Glennon,Joanna Widomska

doi:10.1038/s41598-018-28372-3

Abstract

Increased glucocorticoid concentrations have been shown to favor resilience towards autoimmune phenomena. Here, we addressed whether experimentally induced elevations in circulating glucocorticoids mitigate the abnormalities exhibited by an experimental model of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). This is a pathogenic hypothesis linking repeated exposures to Group-A-beta-hemolytic streptococcus (GAS), autoantibodies targeting selected brain nuclei and neurobehavioral abnormalities. To persistently elevate glucocorticoid concentrations, we supplemented lactating SJL/J mice with corticosterone (CORT; 80 mg/L) in the drinking water. Starting in adolescence (postnatal day 28), developing offspring were exposed to four injections - at bi-weekly intervals - of a GAS homogenate and tested for behavioral, immunological, neurochemical and molecular alterations. GAS mice showed increased perseverative behavior, impaired sensorimotor gating, reduced reactivity to a serotonergic agonist and inflammatory infiltrates in the anterior diencephalon. Neonatal CORT persistently increased circulating glucocorticoids concentrations and counteracted these alterations. Additionally, neonatal CORT increased peripheral and CNS concentrations of the anti-inflammatory cytokine IL-9. Further, upstream regulator analysis of differentially expressed genes in the striatum showed that the regulatory effect of estradiol is inhibited in GAS-treated mice and activated in GAS-treated mice exposed to CORT. These data support the hypothesis that elevations in glucocorticoids may promote central immunomodulatory processes.

Highlights

Neonatal experiences persistently adjust individual adaptation towards future challenges[1]
An analogous increment in CORT concentrations was observed in adulthood, irrespective of Group-A-beta-hemolytic streptococcus (GAS) administration, when we evaluated serum basal CORT concentrations (neonatal treatment: F(1,32) = 4,611, p = 0,0394, see Fig. 2b)
Activity, increased serum protein levels of interleukin 9 (IL-9) paralleled by IL-9+ microglia in the central nervous system (CNS), and changes in striatal gene expression

Summary

Introduction

Neonatal experiences persistently adjust individual adaptation towards future challenges[1]. Tourette’s Syndrome (TS) and Obsessive Compulsive Disorder (OCD) have been proposed to constitute instances of PANDAS: while several studies reported the presence of elevated concentrations of anti-streptococcal antibody titers in TS patients[15], Orlovska et al.[16] demonstrated that streptococcal infections relate to an increased risk of OCD in a Danish nationwide study. Both TS and OCD have been associated with alterations at the level of the basal ganglia[17]. To elucidate the molecular mechanisms underlying the observed phenotypic alterations, we performed RNA sequencing of the striatum, the main component of the basal ganglia that is typically affected in PANDAS17

Methods

Results

Conclusion