Genetically engineered GABA-producing cells demonstrate anticonvulsant effects and long-term transgene expression when transplanted into the central piriform cortex of rats
Genetically engineered GABA-producing cells demonstrate anticonvulsant effects and long-term transgene expression when transplanted into the central piriform cortex of rats
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DOI：
10.1006/exnr.2002.7914
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发表时间：
2002-07-01
影响因子：
5.3
通讯作者：
Tobin, AJ
中科院分区：
文献类型：
--
作者：
Gernert, M;Thompson, KW;Tobin, AJ
局部应用GABA增强剂可预防或减少边缘系统点燃大鼠行为性癫痫发作的发生和维持。显微注射和损伤的研究表明，前和后梨状皮质（PC）之间的过渡区，这里称为中央PC，是一个潜在的目标GABA产生细胞的移植。在本研究中，我们将条件永生化的小鼠皮质神经元（用GABA合成酶GAD（65）改造）移植到大鼠的中央PC。将1穆尔中的1.5 × 10（5）个细胞的悬浮液双侧移植。对照动物接受β-半乳糖苷酶（β-gal）表达细胞的移植。所有大鼠随后点燃通过长期植入电极放置在基底外侧杏仁核。点燃前和点燃后的阈值电流诱发行为发作前和后测定。我们发现，与接受β-半乳糖生产细胞移植的大鼠相比，接受GABA生产细胞的大鼠的预点燃部分癫痫发作阈值显著增加约200%。点燃后，癫痫发作阈值往往是100%的大鼠接受GABA产生细胞，虽然与对照组的差异没有统计学意义。GABA产生的移植物对杏仁核点燃率没有显著影响，但在接受GABA产生细胞的动物中，点燃期间第一次全身性癫痫发作的潜伏期显著增加。移植的细胞显示出长期GAD（65）表达，如实验终止后免疫组织学证实的。研究结果证实和扩展以前的研究结果，中央PC的解剖基质的一部分，有利于传播从部分到全面的癫痫发作。这些数据表明，基因工程细胞有可能提高癫痫发作阈值时，移植到中央PC。(C)2002 Elsevier Science（美国）。
Local application of GABA-potentiating agents can prevent or reduce the development and maintenance of behavioral seizures induced by limbic kindling in rats. Microinjection and lesion studies suggest that the transition zone between anterior and posterior piriform cortex (PC), termed here central PC, is a potential target for transplantation of GABA-producing cells. In the present study, we transplanted conditionally immortalized mouse cortical neurons, engineered with the GABA-synthesizing enzyme GAD(65) to the central PC of rats. Suspensions of 1.5 X 10(5) cells in 1 mul were transplanted bilaterally. Control animals received transplantation of beta-galactosidase (beta-gal)-expressing cells. All rats were subsequently kindled through a chronically implanted electrode placed in the basolateral amygdala. The pre- and postkindling threshold currents for eliciting behavioral seizures were determined before and after kindling. We found the prekindling partial seizure threshold to be significantly increased by about 200% in the rats that received the GABA-producing cells compared to rats receiving beta-gal-producing transplants. After kindling, the seizure threshold tended to be higher by 100% in rats that received GABA-producing cells, although the difference from controls was not statistically significant. GABA-producing transplants had no significant effect on the rate of amygdala kindling, but the latency to the first generalized seizure during kindling was significantly increased in animals receiving GABA-producing cells. The transplanted cells showed long-term GAD(65) expression as verified immunohistologically after termination of the experiments. The findings substantiate and extend previous findings that the central PC is part of the anatomical substrate that facilitates propagation from partial to generalized seizures. The data demonstrate that genetically engineered cells have the potential to raise seizure thresholds when transplanted to the central PC. (C) 2002 Elsevier Science (USA).