MULTIPLE KAINIC ACID SEIZURES IN THE IMMATURE AND ADULT BRAIN - ICTALMANIFESTATIONS AND LONG-TERM EFFECTS ON LEARNING AND MEMORY

Purpose: While there is increasing evidence that the adverse effects o f prolonged seizures are less pronounced in the immature than in the m ature brain, there have been few investigations of the long-term effec ts of recurrent seizures during development. This study examined the e ffects of multiple administrations of the convulsant kainic acid (KA) on seizure characteristics and spatial learning as a function of brain development. Methods: To determine the long-term effects of serial KA seizures during ontogeny, saline or convulsant doses of KA were given intraperitoneally 4 times, at 2-day intervals. Immature rats were giv en KA on P20, P22, P24 and P26; adult rats got KA on P60, P62, P64 and P66. Ictal characteristics and EEGs were recorded. To examine the eff ects of multiple KA seizures on the retention of spatial learning, wat er maze testing was performed before (immature group: from P16-19, adu lt group: from P56-P59) and after (immature: from P60-P63, adult: from P100-P103) KA injections. Finally, histology was performed to compare KA-induced damage at each age. Results: In immature animals, serial K A administration resulted in seizures with a progressively longer onse t latency and decreased severity. In contrast, KA serially administere d to adult rats caused severe seizures after each of the 4 injections. In immature rats, epileptiform EEG changes were most prominent after the first KA injection, whereas in adults, prolonged paroxysmal EEG pa tterns were seen after all 4 KA injections. Before KA, both rat pups a nd adults acquired place learning in the water maze. One month after t he final KA injection, there was no deficit in spatial learning retent ion in the immature group, whereas the adult group had profound impair ment compared to age-matched, saline-injected controls. Histology reve aled no lesions in immature rats treated multiple times with KA but pr ofound cell loss in hippocampal fields CA4, CA3 and CA1 in rats treate d serially with KA as adults. Conclusions: Previous studies have shown that a single KA injection causes prolonged status epilepticus (which persists for several hours), leading to severe histologic and behavio ral sequelae in adult rats but not in pups. Our study extends those fi ndings, demonstrating that immature rats are spared the cognitive and pathological sequelae of multiple injections of convulsant doses of KA as well.