Possible role of hyperpolarization-activated cation (HCN) channels in the generation of absence seizures.
| Project/Area Number |
15591140
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Nippon Medical School |
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Principal Investigator |
MARU Eiichi Nippon Medical School, Associate Professor, 医学部, 助教授 (80221597)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAGATA Kanato Tokyo Metropolitan Institute for Neuroscience, Director of Neuropharmacology Department, 東京都神経科学総合研究所・神経薬理学, 副参事研究員 (20263262)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Absence epileptic seizures / hyperpolarization-activated cation channels / HCN2 subunit / ZD7288 / spike and wave discharge(SWD) / spontaneously epileptic rat(SER) / γ-butyrolactone / kindling / 欠神発作 / 遺伝性てんかんラット / SER / spike and wave discharge / 免疫染色法 / ラット / γ-hydroxybutyric acid |
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| Research Abstract |
Absence seizure, a form of idiopathic generalized epilepsy, is characterized by a brief loss of consciousness (behavioral arrest) associated with EEG recordings of spike and wave discharges(SWDs). Previous studies have demonstrated that the rhythmic bursting activity produced by the thalamocortical neural network is critical for the generation of SWD characteristic of absence epilepsy. Because HCN2, a subunit of the hyperpolarization-activatied cation (HCN) channel, -deficient mice exhibit spontaneous absence seizures, we examined the possible role of HCN channels in the generation of absence seizures in the following 3 experiments.
1.Intracerebroventricularly administered ZD7288 (more than 500 μM, 4 μL), a HCN channel blocker, induce behaviorally sudden arrests and SWDs frequently in normal Wistar-strain rats. ZD7288-induced epileptic EEG patterns were quite similar to the SWDs and sustained rhythmic slow waves induced by γ-butyrolactone (GBL).
2.Effects of the HCN channel blocker on the strength of partial epileptic seizures was examined in the amygdala kindled rat, a well-known animal model of partial epilepsy. ZD7288 (500 μM,4 μL) had no significant effects on the duration of afterdischarge in amygdala kindled rats, when injected intracerebroventriclularly 30 min previously.
3.The expression of HCN2 protein was examined immunochemically in the thalamus of spontaneously epileptic rats(SER), double mutants (zi/zi and tm/tm) showing absence-like seizures. HCN2 protein expression was significantly lower in the thalamus of SERs than in that of Wistar control rats.
When absence seizures were induced by GBL in non-epileptic Wistar rats, the expression of HCN2 was significantly up-regulated in the thalamus 2-3 days after the absence seizures.
These results indicate that HCN channels prevent intrinsically the generation of absence seizures, and its expression in the thalamic nuclei is dynamically regulated by seizure acivities.
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Report
(3 results)
Research Products
(5 results)
