Abstracts

RATIONALE: Dentate granule cell neurogenesis is stimulated by seizures in adult rats, but decreased in young pups. Corticosteroid (CORT) plasma levels increase significantly on postnatal (P) day 14 and again on P21, ages associated with a natural decline in neurogenesis. We hypothesized that elevated CORT plasma levels could be induced and sustained by perinatal seizures during the hyporesponsive period and contribute to inhibition of neurogenesis.
METHODS: Status epilepticus was induced with kainate (KA) one, two or three times at postnatal ages (P6, P9, P13 or P20 or P30) and rats were sacrificed 48 hrs after the last seizure. Glucocorticosteroid levels were measured with radioimmunoassay (RIA). Neurogenesis was assessed by single and double-labeling with bromodeoxyuridine (BrdU) immunohistochemistry. Electrographic activity (EEG) was recorded at P13, P20, and P30 in the presence and absence of a history of perinatal seizures induced by KA.
RESULTS: In control P6 animals, basal CORT levels were low (0.06 [plusminus] 0.1 mg/dL), increased steadily, and then rose sharply between P20-P22 (4.07 [plusminus] 0.6 to 16.1 [plusminus] 0.46 mg/dL). At least three episodes of sustained status epilepticus within the first 13 days of postnatal life were required to suppress granule cell neurogenesis. Suppression was not due to cell death as chromatin stains only showed increased basophilia of inner cells lining the granule cell layers, in the absence of eosinophilia, argyrophilia, or TUNEL labeling. The EEG also showed no relationship between neurogenesis and duration of high-synchronous ictal activity at the postnatal ages examined. In contrast, endocrine studies showed sustained increases at 1 hr after status epilepticus in circulating CORT levels following 1xKA on P6 (0.7[plusminus] 0.1 to 2.40 [plusminus] 0.86 [mu]g/dL) or 2xKA on P6 and P9 (10 [plusminus] 0.77 [mu]g/dL). Following 3xKA on P6, P9, and P13 or P20, cumulative increases exceeded 10 [mu]g/dL and these were sustained even after 4-8 hrs.
CONCLUSIONS: Perinatal seizures inhibit neurogenesis if (1) a certain number of seizures are first initiated during active phases of granule cell proliferation and migration and (2) a minimal level of circulating plasma CORT is reached and sustained. It is proposed that control of dentate granule cell neurogenesis with early intervention by regulation of post-ictal CORT levels with CORT suppression may help prevent deleterious side effects of seizures in young humans.
[Supported by: NIH-NS-38069]