White Matter Injury and Autistic-Like Behavior Predominantly Affecting Male Rat Offspring Exposed to Group B Streptococcal Maternal Inflammation

Abstract

The impact of the group B streptococcus (GBS)-induced maternal inflammation on offspring's brain has not yet been investigated despite GBS being one of the most frequent bacteria colonizing or infecting pregnant women. According to our hypothesis GBS-induced maternal immune activation plays a role in offspring perinatal brain damage and subsequent neurodisabilities such as autism. Using a new preclinical rat model of maternal inflammation triggered by inactivated GBS, we demonstrated placental, neuropathological and behavioral impacts on offspring. GBS-exposed placentas presented cystic lesions and polymorphonuclear infiltration located within the decidual/maternal side of the placenta, contrasting with macrophagic infiltration and necrotic areas located in the labyrinth/fetal compartment of the placenta after lipopolysaccharide-induced maternal inflammation. Brain damage featured lateral ventricles widening, predominately in the male, reduction of periventricular external capsules thickness, oligodendrocyte loss, and disorganization of frontoparietal subcortical tissue with no glial proliferation. Autistic hallmarks were found in offspring exposed to GBS, namely deficits in motor behavior, social and communicative impairments, i.e. profound defects in the integration and response to both acoustic and chemical signals that are predominant modes of communication in rats. Surprisingly, only male offspring were affected by these combined autistic-like traits. Our results show for the first time that materno-fetal inflammatory response to GBS plays a role in the induction of placental and cerebral insults, remarkably recapitulating cardinal features of human autism such as gender dichotomy and neurobehavioral traits. Unlike other models of prenatal inflammatory brain damage (induced by viral/toll-like receptor 3 (TLR3) or Gram-negative/TLR4), maternal inflammation resulting from GBS/TLR2 interactions induced a distinctive pattern of chorioamnionitis and cerebral injuries. These results also provide important evidence that beyond genetic influences, modifiable environmental factors play a role in both the occurrence of autism and its gender imbalance.

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

“…Antenatal infections are recognized as an important risk factor for adverse outcome in term and preterm neonates [27,28,29,30,31,32,33,34,35]. The combined exposure to perinatal inflammation and neonatal HI results in a complex interplay of various signaling pathways of which the exact underlying mechanism has not been elucidated yet.…”

Mild intermittent hypoxemia in neonatal mice causes permanent neurofunctional deficit and white matter hypomyelination

“…An olfactory discrimination test, adapted to the p10 mouse pups, was performed as described (Bergeron et al, 2013;Schneider and Przewlocki, 2005). This test is based on nest-seeking behavior mediated by the olfactory system (Gregory and Pfaff, 1971).…”

A Critical Review of Models of Perinatal Infection

“…In this model, E. coli exposure (3-4 × 10 7 colony-forming units, CFU) was associated with increased fetal reabsorption/stillbirth, while surviving pups exhibited an increase in brain chemokines/cytokines and a range of no to severe white matter injury, including oligodendrocyte cell death, astrogliosis and microgliosis [26,27,28,29]. Maternal inflammation induced by intraperitoneal administration of inactivated GBS (1 × 10 9 CFU) to pregnant rats was also associated with histological aseptic chorioamnionitis, white matter injury, and long-term behavioral (autism-like) deficits in the offspring [30]. Further, although it is relatively less invasive, Ureaplasma has been associated with preterm birth.…”