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.

纹状体是巴萨神经神经回路的中心结构，它介导了各种大脑功能，包括运动控制，运动学习和奖励相关的行为。它包含一些GABA能中的神经元类型，它们的形态和电生理特性不同。但是，其行为和身体角色的差异仍然未知。在本研究中，我们提出了研究两种含有生长抑素（SST）或白蛋白（PVA）的两种海峡GABA能中神经元类型的作用。我们利用免疫毒素细胞靶向消除了神经元回路的特定神经元类型，并研究了所得的表型变化。为了消除含有SST的纹状体GABA能中间神经元，我们生成了突变小鼠，其中将人白细胞介素-2受体A-亚基（IL-2Rα）基因盒引入小鼠前肉毒蛋白酶抑素基因座。将这些小鼠与重组免疫毒素内注射，并减少突变体中靶神经元的数量。突变体的表型分析表明，含SST的GABA能中神经元在抑制赞助运动行为中起着重要作用。此外，为了消除含有PVA的尖锐的GABA能中神经元，我们试图产生突变小鼠，其中将人IL-2Rα盒引入小鼠PVA基因基因座中。敲入靶向载体被引入胚胎茎（ES）细胞中，并用PCR和Southern印迹杂交筛选携带靶突变的细胞。我们成功地获得了携带靶向突变的多个ES细胞。使用这些细胞，我们计划生成敲入突变小鼠并执行免疫毒素细胞靶向，以阐明含有PVA的纹状体GABA能中神经元的行为和身体作用。