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

自发性癫痫大鼠（SER: tm/tm, zi/zi）是由来自京都Wistar群体的震颤大鼠（tm/tm）与来自SD大鼠克隆的震颤大鼠（zi/zi）的杂合子交配获得的。8周后，SER显示缺失样癫痫发作和强直性惊厥。我们之前发现tm和zi基因分别位于10q24和3q35上。根据我们1999-2001年的研究，得到以下结果：(1)天冬氨酸乙酰化酶基因（ASPA）在tm基因区表达缺失，导致震颤大鼠和SER脑内l-乙酰-天冬氨酸（NAA）升高。(2) NAA通过代谢性谷氨酸受体诱导正常大鼠海马CA3神经元向内电流。(3)腺病毒ASPA重组基因注入震颤大鼠侧脑室可减少癫痫发作。这些发现表明，由ASPA延迟引起的NAA增加是震颤大鼠和SER癫痫发作的原因。此外，(4)单次刺激苔藓纤维可选择性地增强SER海马CA3神经元中的CA^<2+>包涵体。(5) Vigabatrin是GABA转氨酶抑制剂，作用于SER海马CA3神经元的GABA_A受体，而不作用于正常wistar大鼠，诱导双核线可逆电流。这些发现证实了先前的发现，即SER海马CA3神经元具有异常作用的CA^<2+>通道。此外，GABA_A受体的改变如构象在SER海马CA3神经元中被认为是改变的。

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.