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IL-6-induced Fetal Neuroinflammation Upregulates Neuronal Progenitors in the Primordial Dentate Gyrus
Abstract Number: BP-05
Abstract Type: Original Research
Background: Fever during labor is associated with a three-fold increased risk of unexplained neonatal seizures, a four-fold increased risk of cerebral palsy, and a four-fold decrease in intelligence scores. We have developed a model of maternal fever and fetal neuroinflammation, using systemic injection of IL-6 in near-term pregnant rats. We are using this model to test the hypothesis that fetal neuroinflammation results in disregulation of hippocampal development, which may be causal in the appearance of later occurring neurological deficits.
Methods: Six pregnant rats were injected on GD20 with either saline (n=3) or IL-6 (n=3). Three injections of saline, or IL-6 (1ug, 1.5 ug and 2.5 ug), were administered at 30 min. intervals. Core temperature was recorded. Twenty-four hours post injection (GD21), dams were anesthetized and brains of two fetuses from each dam analyzed for histochemistry of Glial Fibrillary Acidic Protein (GFAP), a marker of proliferating Radial Glia. The Optical Density of GFAP radial glial fibers and soma was computed using image analysis software (ImageJ). ANOVA repeated a measure was used for temperature differences. Student T test was used for GFAP staining differences. P<0.05 was considered statistically significant.
Results: Compared to saline, IL-6 injections resulted in a significant temperature difference (saline 37.1 ± 0.17 C and IL-6 37.5 ± 0.18), p<0.05. Within the hippocampus, proliferation of neural progenitors, identified by the extensive processes of neuroprogenitor radial glia, was primarily localized to the primordial dentate gyrus. Optical density analyses of GFAP label radial glia in the dentate gyrus showed a greater than 40% increase in radial glia soma and processes (p< .01) in IL6-exposed vs. Saline-exposed fetal brains.
Discussion: In fetuses at GD 20 hippocampal development, CA1/CA3 migration and proliferation are minimally developed. In contrast, GD20 is a time of critical development for dentate gyrus. Since the dentate gyrus is a critical component of the hippocampal memory processing circuit, disruption of the normal level of dentate proliferation is likely to produce memory related cognitive deficits during later development. These data provide insights into the role of neuroinflammation in hippocampal development. Future studies will be targeted at identification of inflammatory factors that alter neuronal proliferation.
This study was supported by the Department of Anesthesiology, Tufts Medical Center, and the Saltonstall Foundation.