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 as sociated 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.Speci fically, the effects of prolonged prenatal stress on seizure susceptibility and the mechanisms underlying this asso ciation remain unclear.Purpose: Infantile spasms, also known as West syndrome, are agespecific epileptic seizures.Most affected patients exhibit signs of delayed development.Using a pharmacolo gically induced NmethylDaspartate (NMDA)induced spasmlike seizure model, this study aimed to determine whether longterm prenatal stress increases susceptibility to these spasmlike events and examine the associated changes in glial activation and gammaaminobutyric acid (GABA)ergic signaling.Methods: Pregnant SpragueDawley rats were subjected to acute immobilization stress (AIS; single 45min restraint on gestational day 15) or chronic immobilization stress (CIS; daily 2hour 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 spasmlike behavior was scored 75 minutes after the injection by an observer blinded to the group assign ment.Immunohisto chemical, quantitative reverse transcription polymerase chain reaction, and Sholl analyses were performed to assess glial activation and GABArelated protein expression.Results: We observed that exposure to longterm prenatal stress increased spasm frequency and decreased latency to spasm onset compared to exposure to shortterm prenatal stress.Prenatal immobilization stress increased seizure susceptibility to NMDAtriggered spasms on post natal 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: Longterm prenatal stress, particularly CIS, enhances susceptibility to NMDAinduced spasmlike 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.