Prenatal stress via chronic immobilization amplifies N-methyl-D-aspartate-induced spasm-like seizure susceptibility and neuroinflammation in neonatal rats.

BACKGROUND: Prolonged stress during pregnancy is associated with various neurodevelopmental abnormalities and an increased risk of neurological disorders. Although prenatal stress is implicated in altered brain development, its contribution to infant seizures remains unclear. Specifically, the effects of prolonged prenatal stress on seizure susceptibility and the mechanisms underlying this association remain unclear. PURPOSE: Infantile spasms, also known as West syndrome, are age-specific epileptic seizures. Most affected patients exhibit signs of delayed development. Using a pharmacologically induced N-methyl-D-aspartate (NMDA)-induced spasm-like seizure model, this study aimed to determine whether long-term prenatal stress increases susceptibility to these spasm-like events and examine the associated changes in glial activation and gamma-aminobutyric acid (GABA)ergic signaling. METHODS: Pregnant Sprague-Dawley rats were subjected to acute immobilization stress (AIS; single 45-min restraint on gestational day 15) or chronic immobilization stress (CIS; daily 2-hour restraint on gestational days 15-19). Their offspring were assigned to the control, AIS, and CIS groups. NMDA (15 mg/kg, intraperitoneal) was administered to the resulting offspring on postnatal day 15, and spasm-like behavior was scored 75 minutes after the injection by an observer blinded to the group assignment. Immunohistochemical, quantitative reverse transcription polymerase chain reaction, and Sholl analyses were performed to assess glial activation and GABA-related protein expression. RESULTS: We observed that exposure to long-term prenatal stress increased spasm frequency and decreased latency to spasm onset compared to exposure to short-term prenatal stress. Prenatal immobilization stress increased seizure susceptibility to NMDA-triggered spasms on postnatal day 15 and markedly increased microglial activation in the hippocampus. These findings were observed in acute and CIS models and were accompanied by increased microglial and astrocyte activation and decreased GAD67 expression. CONCLUSION: Long-term prenatal stress, particularly CIS, enhances susceptibility to NMDA-induced spasm-like seizures and is associated with enhanced glial activation and altered GABAergic signaling. As the present findings are associative, further studies are needed to determine whether neuroinflammation and GABAergic dysfunction causally contribute to the increased susceptibility.