Abstracts

Rationale: Although the immature brain is relatively resistant to seizure-induced damage, increasing evidence suggests that neonatal seizures enhance seizure-induced injury later in life. Methods: To determine whether neonatal seizures shift the window of neuronal vulnerability to an earlier age and whether this period corresponds with loss of GluR2 receptors, status epilepticus was induced with kainate (KA) twice or three times at postnatal ages (P6, P9, or P20) with a regimen of three doses at the older age. Young rats were sacrificed 3 or 6 days after the last seizure. Results: Silver impregnation, TUNEL, and immunocytochemistry methods showed hippocampal injury was absent and AMPA and NR1 proteins were unaltered after one KA seizure episode at ages P6 or P9 and at 3 days. At P20 and after a single high dose of KA (10 mg/kg), most CA1 neurons were TUNEL positive or accumulated silver ions, whereas the CA3 was only partly labeled at either time point. At a middle dose of KA (7 mg/kg) which induces behavioral seizures lacking several stage 5/6 symptoms (eg. forelimb clonus, generalized tonic-clonic activity and loss of postural tone), TUNEL or silver staining was restricted to CA1 neurons at both time points. No damage was observed at the lower dose (5 mg/kg). Previous exposure to one or two KA seizures had no effect on TUNEL or silver staining patterns. Except for GluR2, glutamate immunolabeling was relatively stable indicating neurons were viable in CA1 despite histological detection of injury. GluR2 immunoreactivity also declined in CA3 after 3 days at the high dose. Conclusion: Results suggest that the pattern of neuronal injury is not influenced by previous history of neonatal seizures but by intensity of activity and maturation of excitatory anatomy and function. GluR2 downregulation in CA3 corresponds with intense neuronal activity and first appearance of neuropathology, which may contribute to increased vulnerability if seizures occur during or after the third postnatal week. (Supported by NIH-NS-38069-02)