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Behavioral and physiological roles of the striatal GABAergic interneuronal types

纹状体 GABA 能中间神经元类型的行为和生理作用

基本信息

批准号：
16300102
负责人：
KOBAYASHI Kazuto
金额：
$ 7.17万
依托单位：
Fukushima Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

The striatum is a central structure of the basal ganglia neural circuitry that mediates a variety of brain functions including motor control, motor learning, and reward-associated behavior. It contains some GABAergic interneuronal types that are different in their morphology and electrophysiological property. However, the difference in their behavioral and physiological roles remains unknown. In the present study, we addressed to study the roles of two kinds of straital GABAergic interneuronal types containing somatostatin (SST) or parvalbumin (PVA). We utilized immunotoxin cell targeting to eliminate the specific neuronal type from the neural circuitry and studied the resultant phenotypic changes. To eliminate the striatal GABAergic interneurons containing SST, we generated the mutant mice in which the human interleukin-2 receptor a-subunit (IL-2Rα) gene cassette was introduced into the mouse preprosomatostatin gene locus. These mice were injected intrastriatally with the recombinant immunotoxin, and the number of target neurons were reduced in the mutants. Phenotypic analysis of the mutants indicated that the SST-containing GABAergic interneurons play an important role in suppression of spontaneous motor behavior. In addition, to eliminate the straital GABAergic interneurons containing PVA we tried to produce the mutant mice in which the human IL-2Rα cassette was introduced into the mouse PVA gene locus. The knock-in targeting vector was introduced into embryonic stem (ES) cells, and the cells carrying the targeted mutation were screened with PCR and southern blot hybridization. We succeeded in obtaining multiple ES cells carrying the targeted mutation. Using these cells we are planning to generate the knock-in mutant mice and perform immunotoxin cell targeting to elucidate the behavioral and physiological roles of the striatal GABAergic interneurons containing PVA.

纹状体是基底神经节神经回路的中心结构，介导多种脑功能，包括运动控制、运动学习和奖励相关行为。它包含一些在形态和电生理特性上不同的gaba能神经元类型。然而，它们在行为和生理作用上的差异尚不清楚。在本研究中，我们探讨了两种含有生长抑素（SST）或小白蛋白（PVA）的皮质gaba能神经元间类型的作用。我们利用免疫毒素细胞靶向从神经回路中消除特定的神经元类型，并研究了由此产生的表型变化。为了消除含有SST的纹状体gaba能中间神经元，我们将人白细胞介素-2受体a亚基（IL-2Rα）基因盒引入到小鼠促生长抑素前基因位点，产生突变小鼠。在这些小鼠的胃内注射重组免疫毒素，突变体的目标神经元数量减少。突变体的表型分析表明，含有sst的gaba能中间神经元在抑制自发性运动行为中起重要作用。此外，为了消除含有PVA的条带gaba能中间神经元，我们试图将人IL-2Rα盒体引入小鼠PVA基因位点，从而产生突变小鼠。将敲入靶向载体导入胚胎干细胞，采用PCR和southern blot杂交技术筛选携带靶向突变的细胞。我们成功地获得了多个携带目标突变的胚胎干细胞。我们计划利用这些细胞产生敲入突变小鼠，并进行免疫毒素细胞靶向，以阐明含有PVA的纹状体gaba能中间神经元的行为和生理作用。