Abstracts

During a critical developmental period associated with marked surges in glucocorticosteroids (CORT), neurogenesis of the hippocampus is constrained by multiple perinatal seizures.
To determine whether CORT plays a role in the suppression, ADX was performed on postnatal (P) day 5 followed by three injections of KA (3xKA) on P7, P9, and P13. Metyrapone, a CORT synthesis inhibitor, was also administered (50 mg/ml) 30 min prior to the KA injections. At 48 hrs, blood was drawn from experimental animals and age-matched controls following decapitation. BrdU immunohistochemistry was performed in coronal sections from all animals.
After 3xKA, sustained elevations in plasma CORT levels were observed as determined by radioimmunoassay (RIA). ADX and metyrapone prevented seizure-induced surges in circulating plasma CORT (ADX + KA: 0.132 [plusmn] 0.088 [micro]g/dL vs. sham + CORT: 3.126 [plusmn] 8 [micro]g/dL vs. Sham + KA: 6.34 [plusmn] 0.551[micro]g/dL). Control numbers of BrdU-labeled cells were observed following ADX alone (ADX: 497 [plusmn] 6, vs. na[iuml]ve control 485 [plusmn] 8). Sham operated controls with 3xKA showed marked decreases in BrdU-labeled cells, whereas rat pups with ADX + 3xKA had control numbers (ADX+KA: 490 [plusmn] 2 vs. sham +3xKA, 219 [plusmn] 10). Similarly, metyrapone treated rat pups had control levels of BrdU-labeled cells after 3xKA and 48 hrs (519 [plusmn] 5). CORT replacement reversed the protective effects of ADX. Chromatin, TUNEL and silver stains showed no histological change in the hippocampus or other brain structures after ADX or sham operation.
It appears that perinatal seizures increase circulating CORT levels to a critical level that interferes with dentate granule cell division independent of cell death and in an age-dependent fashion.
[Supported by: NJ Neuroscience Insitute and NS 38069 to LKF.]