Abstracts

RATIONALE: The paradoxical mechanisms underlying a reduced seizure threshold during the first 2 weeks of postnatal (P) life and increased threshold during the 3rd-4th weeks are unknown. In adult rats, kindled seizures increase metabotropic glutamate receptor (mGluR) I mRNA expression of hippocampal pyramidal cells whereas mGluR II subtype hyperpolarizations are reduced possibly leading to a reduction in the seizure threshold and development of spontaneous seizures in the mature brain. After the 2nd postnatal week, mGluR1 specific agonist, 3,5-DHPG, induces seizures and preferential CA1 injury. However, maturational expression of mGluR proteins in response to a varied seizure history has not been previously explored.
METHODS: To study the consequences of sustained recurrent seizures on maturational expression of mGluR proteins and the seizure threshold over time, a series of KA seizure episodes were induced either once or three times on P6, P9, and P14 or P21. Animals were sacrificed 48 hrs after 1xKA or 3xKA at the four ages. Brains were examined with specific group I and group II antibodies. Electrographic activity (EEG) was recorded in the P14 and P21 rats.
RESULTS: In PBS injected age-matched controls, mGluR1 hippocampal immunolabeling patterns were developmentally regulated. At P6 pyramidal and dentate granule layers were labeled uniformly. At P9, mGluR1 intense labeling occurred only within inhibitory interneurons of the subiculm/CA1 stratum oriens molecular layer. At P14 and P21, interneurons were also labeled in other regions and CA3 pyramidal cells were faint. In adults, as previously reported, neuropilar staining of the CA3 and dentate hilus was robust and CA1 interneurons continued to label. In contrast, mGluR2 and mGluR5 protein patterns were mature by P14. After 1xKA, there was no apparent change in the expression of group I or group II antibody labeling intensities or patterns at the young ages examined. In contrast, P14 rats with 3xKA showed selective increases in mGluR1 protein within inhibitory interneurons of the CA1 stratum oriens and subiculum, particularly within the dendritic network. Interestingly, in the EEG, the appearance of long high-synchronous events and frequency amplitude were significantly increased in animals at P14 but reduced at P20 despite that they had the same history of perinatal seizures.
CONCLUSIONS: Maturational differences in mGluR1 expression may influence the endogenous switch in seizure susceptibility. Upregulation of mGluR group I receptors within CA1 hippocampal inhibitory interneurons induced by repetitive perinatal seizures may provide an adaptive mechanism by raising the inhibitory drive of the hippocampus after a certain age via increased interneuronal release of GABA due to repeated seizure-induced glutamate stimulation.
[Supported by: NIH-NS-38069]