| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
In this study, I examined the involvement of the GABA_B receptors and the coordinated induction of nuclear transcription factors in generalized absence seizures in lethargic (lh/lh) and stargazer (stg/stg) mice, genetic models of absence seizures. electroencephalographic recordings of lethargic and stargazer mice revealed 6 Hz spike and wave discharges (SWD_S) accompanied by simultaneous arrest of movement for the duration of the SWDs. Ethosuximide, a typical antiabsence drug, and CGP 35348 and CGP 46381, GABA_B antagonist, suppressed SWD_S in both models Gel-shift assays showed that nuclear cyclic AMP responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in the thalamus and cerebral cortex, but not in other regions such as the cerebellum of lethargic and stargazer mice were significantly higher than those of each nonepileptic control (+/+) mice. The CRE- and AP-1 DNA-binding activities in both model mice, but not control mice, were inhibited by ethosuximide or CGP 46831, at a dose which suppressed SWD_S. These results suggest that GABA_B receptors play a significant role in the pathogenesis of generalized absence seizures and that enhanced nuclear CRE- and AP-1 DNA-binding activities in the thalamocortical region are related to generation and/or propagation of absence seizures in lethargic and stargazer mice. Furthermore, cerebral cortical CRE-binding activity was supershifted by the anti-GRE-binding protein (CREB) antibody and partially inhibited by anti-phospho-CREB antibody in lethargic mice. The AP-1 DNA-binding activity was inhibited by anti-c-Fos and anti-c-Jun antibodies.These results suggest that the enhanced CRE-binding activity is attributable to the activation of the binding activity of CREB which is phosphorylated at least in part and that the c-Fos-c-Jun complex (AP-1 protein) is a major component of the enhanced AP-1 DNA-binding activity.
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