Maternal Noninfectious Fever Enhances Cell Proliferation and Microglial Activation in the Neonatal Rat Dentate Gyrus

Fever and increased maternal interleukin-6 (IL-6) plasma levels in labor are associated with an increased risk of adverse events in offspring, including neonatal seizures, cerebral palsy, and low intelligence scores at school age. However, the neural changes in the neonate that might mediate the adverse effects of maternal noninfectious fever are not fully characterized. This study was designed to test the hypothesis that induced maternal noninfectious fever alters neonatal neural progenitor cell proliferation and enhances microglial activation in the rat dentate gyrus of the hippocampus.

Systemic vehicle or IL-6 was given 3 times to near-term pregnant rats (n = 7/group) every 90 minutes, and maternal core temperature was recorded. Neonatal brains were processed and analyzed for dentate gyrus cell proliferation (using Ki-67, n = 10/group, and glial fibrillary acidic protein, n = 6/group) and resident microglia activation (using ionized calcium-binding adaptor protein-1 [Iba-1], n = 6/group). In separate studies, the authors assessed microglia proliferation using Ki-67/Iba-1 costaining (n = 5/group).

Compared to controls, exposure to IL-6 resulted in significant maternal temperature increase [mean temperature difference 0.558°C (95% CI, 0.417-0.698; P < .0001)]. Following maternal IL-6, Ki-67 cell proliferation in the dentate gyrus was 55 % higher in neonates whose mother received IL-6 (38.8 ± 9.2) compared with those that received vehicle (25.1 ± 7.8); mean difference 13.7 (95% CI, 5.68-21.71); (P = .0021). Glial fibrillary acidic protein cell proliferation was 40% higher in the neonatal dentate gyrus whose mother received IL-6 when compared to controls (713 ± 85.52 vs 500 ± 115); mean difference 212 (95% CI, 82.2-343.4); (P = .004). Resident microglial activation was 90% higher in the dentate gyrus of neonates whose mother received IL-6 when compared to controls (71.8 ± 9.3 vs 37.8 ± 5.95); mean Iba-1 in stained cells was significantly different between IL-6 and vehicle groups 34 (95% CI, 23.94-44.05); (P < .0001). Proliferating microglia, determined by the colocalization of Ki-67 and Iba-1, were not different in the vehicle (8.8 % ± 3.19 %) and the IL-6 (5.6% ± 2.3%) groups (mean difference 3.2% (95% CI, -0.8-7.25) (P = .1063).

IL-6 is sufficient to induce maternal systemic temperature increases in near-term pregnant rats as well as neuronal, glial, and neuroinflammatory changes in the dentate gyrus of the neonatal hippocampus. These alterations might disrupt fetal neurodevelopment during a vulnerable period.