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

自发性癫痫大鼠(SER：Tm/tm，zi/zi)是由京都Wistar群体的震颤大鼠(tm/tm)的杂合子与SD大鼠克隆的Zitter大鼠(zi/zi)杂交而成的。8周龄后SER表现为失神样惊厥和强直性惊厥。我们已经发现tm和zi基因分别位于10q24和3q35上。(1)天冬氨酸乙酰基酶基因(Aspa)缺失于tm基因区，导致大鼠海绵体及SER脑组织中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Wistar大鼠海马CA3神经元上诱发内向电流。(3)将ASPA重组腺病毒载体应用于震颤大鼠侧肺，可减少癫痫发作。这些发现表明，ASPA缺失导致的NAA增加与惊厥大鼠和SER的癫痫发作有关。此外，(4)单次刺激苔藓纤维可选择性增强SER大鼠海马CA3区神经元的CA^&lt；2+&gt；exx。(5)GABA转氨酶抑制剂Vigabatrin作用于SER大鼠海马CA3区神经元的GABA_A受体，但不作用于正常Wistar大鼠，诱发双核可逆电流。这些发现证实了以前的发现，即SER海马CA3区神经元具有异常作用的CA^&lt；2+&gt；通道。此外，在SER的CA3区神经元中，GABA_A受体的改变，如构象，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.