GABA-A receptors regulate neocortical neuronal migration in vitro and in vivo
GABA-A receptors regulate neocortical neuronal migration in vitro and in vivo
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DOI：
10.1093/cercor/bhj135
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发表时间：
2007-01-01
期刊：
影响因子：
3.7
通讯作者：
Luhmann, Heiko J.
中科院分区：
文献类型：
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作者：
Heck, Nicolas;Kilb, Werner;Luhmann, Heiko J.
皮质迁移过程取决于许多营养因子以及不同电压门控通道和配体门控通道的激活。我们在体内和体外研究了γ-氨基丁酸（GABA）A 型受体在新生大鼠顶叶皮层神经元迁移过程中的作用。与未经治疗或假手术对照相比，通过皮质表面 Elvax 植入物局部体内应用 GABA-A 拮抗剂荷包牡丹碱 (BMI) 或激动剂蝇蕈醇可引起皮质结构的显着改变。 BMI 和蝇蕈醇治疗的动物显示上层存在异位细胞簇，并且 Elvax 植入物下方区域的皮质层压完全丧失。神经胶质纤维酸性蛋白、N-甲基-D-天冬氨酸受体和 GABA 的免疫细胞化学染色表明，异位不是由神经胶质细胞增殖引起的，并证实了谷氨酸能和 GABA 能神经元的存在。在来自第 18-19 天胚胎的器官型新皮质切片中，BMI 和较小程度的蝇蕈醇的应用诱导了上皮质层中神经元迁移速度的增加和积累。新生大鼠新皮质切片中自发的细胞内钙 ([Ca2+](i)) 振荡被 BMI（5 和 20 μM）和蝇蕈醇（1 和 10 μM）消除，表明这两种化合物都会干扰正常神经元迁移所需的 [Ca2+](i) 信号传导。新生大鼠新皮质切片中迁移神经元的电生理记录表明，长期应用蝇蕈醇会由于明显的受体脱敏而导致突触后 GABA-A 受体的反应性显着降低（1 μM 蝇蕈醇）或阻断（10 μM）。我们的结果表明，作为激动剂或拮抗剂的化合物对 GABA-A 受体的调节可能会深刻影响发育中的大脑皮层中的神经元迁移过程。
The cortical migration process depends on a number of trophic factors and on the activation of different voltage- and ligand-gated channels. We investigated the role of gamma-aminobutyric acid (GABA) type A receptors in the neuronal migration process of the newborn rat parietal cortex in vivo and in vitro. Local in vivo application of the GABA-A antagonist bicuculline methiodide (BMI) or the agonist muscimol via cortical surface Elvax implants induced prominent alterations in the cortical architecture when compared with untreated or sham-operated controls. BMI- and muscimol-treated animals revealed heterotopic cell clusters in the upper layers and a complete loss of the cortical lamination in the region underlying the Elvax implant. Immunocytochemical staining for glial fibrillary acidic protein, N-methyl-D-aspartate receptors, and GABA demonstrated that heterotopia was not provoked by glial proliferation and confirmed the presence of both glutamatergic and GABAergic neurons. In organotypic neocortical slices from embryonic day 18-19 embryos, application of BMI and to a lesser extent also muscimol induced an increase in the migration speed and an accumulation of neurons in the upper cortical layers. Spontaneous intracellular calcium ([Ca2+](i)) oscillations in neocortical slices from newborn rats were abolished by BMI (5 and 20 mu M) and muscimol (1 and 10 mu M), indicating that both compounds interfere with [Ca2+](i) signaling required for normal neuronal migration. Electro-physiological recordings from migrating neurons in newborn rat neocortical slices indicate that long-term application of muscimol causes a pronounced reduction (1 mu M muscimol) or blockade (10 mu M) in the responsiveness of postsynaptic GABA-A receptors due to a pronounced receptor desensitization. Our results indicate that modulation of GABA-A receptors by compounds acting as agonists or antagonists may profoundly influence the neuronal migration process in the developing cerebral cortex.