Pharmacological research on Ca^<2+> channel abnormality which induces epileptic seizures

通过将来自京都Wistar大鼠群的震颤大鼠（tm/tm）的杂合子与来自SD大鼠群的zitter大鼠（zi/zi）交配，获得自发性癫痫大鼠（SER：tm/tm，zi/zi）。SER在8周龄后表现为失神样发作和强直性惊厥。我们在1999-2001年的研究中发现tm和zi基因分别位于10 q24和3q 35。(1)天冬氨酸乙酰化酶基因（ASPA）在tm基因区缺失，导致震颤大鼠和SER脑中L-乙酰天冬氨酸（NAA）含量增加。(2)NAA通过代谢型谷氨酸受体在正常wister大鼠海马CA 3区神经元产生内向电流。(3)将ASPA重组腺病毒应用于震颤大鼠的侧脑室导致癫痫发作减少。这些结果表明，ASPA缺失引起的NAA增加是震颤大鼠和SER癫痫发作的原因。（4）单次刺激SER海马CA 3区苔藓纤维可选择性地增强CA^<2+>包涵体。(5)GABA转氨酶抑制剂氨己烯酸（Vigabatrin）作用于SER大鼠海马CA 3区神经元的GABA_A受体，引起荷包牡丹碱可逆电流。这些结果证实了先前的发现，即SER海马CA 3神经元具有异常作用的CA^<2+>通道。此外，SER海马CA 3区神经元GABA_A受体的构象也发生了改变。

The spontaneously epileptic rat (SER : tm/tm, zi/zi) is obtained by mating a heterozygote of the tremor rat (tm/tm) derived from the Kyoto Wistar colony with the zitter rat (zi/zi) from the SD rat clony. The SER shows both absence-like seizures and tonic convulsion after 8 weeks old. We have previously found that tm and zi genes were located on 10q24 and 3q35, respectively.Based on our studies of 1999-2001, the following results were obtained. (1) Aspartacetylase gene (ASPA) was delated in the tm gene region, resulting in an increase of L-acetyl-aspartate (NAA) in the tremora rat and SER brain. (2) NAA induced an inward current in hippocampal CA3 neurons of normal wister rats via metabotropic glutamate receptors. (3) Application of ASPA recommbinant in adenovirlus into the lateral venticle of the tremor rat resulted in a reduction of epileptic seizures. These findings suggest that increased NAA resulting from ASPA delation is responsible for epiletic seizures in tremora rats and SER. Furthermore, (4) selectively enhanced CA^<2+> inclux was observed in the hippocampal CA3 neurons of SER with single stimulation of the mossy fibers. (5) Vigabatrin, which is an inhibitor of GABA transaminase, acted on the GABA_A receptors of hippocampal CA3 neurons of SER, but not normal wistar rats, to induce a bicucculline-reversible current. These findings confirm the previous findings that SER hippocampal CA3 neurons have abnormaly acting CA^<2+> channels. Inaddigion, changes in GABA_A receptor such as conformation are suggested to be altered in SER hippocampal CA3 neurons.