Decreased glutamate receptor 2 expression and enhanced epileptogenesis in immature rat hippocampus after perinatal hypoxia-induced seizures

Hypoxic encephalopathy is the most common cause of neonatal seizures and ca n lead to chronic epilepsy. In rats at postnatal days 10-12 (P10-12), globa l hypoxia induces spontaneous seizures and chronically decreases seizure th reshold, thus mimicking clinical aspects of neonatal hypoxia. We have shown previously that the acute and chronic epileptogenic effects of hypoxia are age-dependent and require AMPA receptor activation. In this study, we aime d to determine whether hypoxia-induced seizures and epileptogenesis are ass ociated with maturational and seizure-induced changes in AMPA receptor comp osition and function. Northern and Western blots indicated that glutamate r eceptor 2 (GluR2) mRNA and protein expression were significantly lower in n eocortex and hippocampus at P10-12 compared with adult. After hypoxia-induc ed seizures at P10, GluR2 mRNA was significantly decreased within 48 hr, an d GluR2 protein was significantly decreased within 96 hr. AMPA-induced Co2 uptake by neurons in hippocampal slices indicated higher expression of Ca2 +-permeable AMPA receptors in immature pyramidal neurons compared with adul t. In slices obtained 96 hr after hypoxia-induced seizures, AMPA-induced Co 2+ uptake was significantly increased compared with age-matched controls, a nd field recordings revealed increased tetanus-induced afterdischarges that could be kindled in the absence of NMDA receptor activation. In situ end l abeling showed no acute or delayed cell death after hypoxia-induced seizure s. Our results indicate that susceptibility to hypoxia-induced seizures occ urs during a developmental stage in which the expression of Ca2+-permeable AMPA receptors is relatively high. Furthermore, perinatal hypoxia-induced s eizures induce increased expression of Ca2+-permeable AMPA receptors and an increased capacity for AMPA receptor-mediated epileptogenesis without indu cing cell death.