Prenatal Infection Decreases Calbindin, Decreases Purkinje Cell Volume and Density and Produces Long-Term Motor Deficits in Sprague-Dawley Rats

Abstract

The cerebellum is involved in the control of motor functions with Purkinje cells serving as the only output from the cerebellum. Purkinje cells are important targets for toxic substances and are vulnerable to prenatal insults. Intrauterine infection (IUI) has been shown to selectively target the developing cerebral white matter through lesioning, necrosis and inflammatory cytokine activation. Developmental and cognitive delays have been associated with animal models of IUI. The aim of this study was to determine if IUI leads to damage to Purkinje cells in the developing cerebellum and if any damage is associated with decreases in calbindin and motor behaviors in surviving pups. Pregnant rats were injected with Escherichia coli (1 × 10⁵ colony-forming units) or sterile saline at gestational day 17. Beginning at postnatal day (PND) 2, the pups were subjected to a series of developmental tests to examine developmental milestones. At PND 16, some pups were sacrificed and their brains extracted and processed for histology or protein studies. Hematoxylin and eosin (HE) staining was done to examine the general morphology of the Purkinje cells and to examine Purkinje cell density, area and volume. Calbindin expression was examined in the cerebellum via immunohistochemistry and Western blot techniques. The remaining rat pups were used to examine motor coordination and balance on a rotating rotarod at the prepubertal and adult ages. Prenatal E. coli injection did not significantly change birth weight or delivery time, but did delay surface righting and negative geotaxis in pups. Pups in the E. coli group also had a decrease in the number of Purkinje cells, as well as a decrease in Purkinje cell density and volume. HE staining demonstrated a change in Purkinje cell morphology. Calbindin expression was decreased in rats from the E. coli group as well. Locomotor tests indicated that while there were no significant changes in gross motor activity, motor coordination and balance was impaired in both prepubertal and adult rats from the E. coli group. In this model of IUI, we observed changes in Purkinje cell development which were associated with alterations in cerebellum-dependent motor behaviors. The decreases in calbindin and Purkinje cells were associated with developmental delays. These data further support the importance of IUI in brain development.

Maternal Immune Activation Produces Cerebellar Hyperplasia and Alterations in Motor and Social Behaviors in Male and Female Mice

“…We report here that cerebellar width, individual ZII+/− PC stripe widths, and PC numbers are increased in prenatally poly(I:C)-exposed offspring of both sexes. Previous findings indicate reduced numbers of PCs following MIA (e.g., [47,63]). In contrast, we find greater numbers of PCs in the poly(I:C)-exposed mice compared to saline controls at all ages tested.…”

Viral infection, inflammation and schizophrenia

“…Rat models of prenatal bacterial infection have also led to structural and biochemical brain abnormalities in the offspring of exposed rats. Recently, Wallace et al (2010) injected pregnant rats with Escherichia coli ( E. coli ) on E17. While prenatal infection with E. coli did not affect birth weight, the authors did observe “surface righting and negative geotaxis” in the offspring (Wallace et al, 2010).…”

“…Recently, Wallace et al (2010) injected pregnant rats with Escherichia coli ( E. coli ) on E17. While prenatal infection with E. coli did not affect birth weight, the authors did observe “surface righting and negative geotaxis” in the offspring (Wallace et al, 2010). Interestingly, infected offspring exhibited reduced Purkinje cell counts, density, and volume, and decreased calbindin, a calcium-binding protein expressed by Purkinje cells in the cerebellum and known for its involvement in motor coordination (Barski et al, 2003).…”

The combined exposure to intra-amniotic inflammation and neonatal respiratory distress syndrome increases the risk of intraventricular hemorrhage in preterm neonates

“…The inflammatory response has been implicated in the genesis of fetal brain injury in humans [1, 5, 15, 29, 30] as well as in experimental animal models [63–67]. However, some recent studies [4, 68–70] reported that acute histologic chorioamnionitis was not an independent risk factor for the development of IVH.…”