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Functional and Phenotypic Regulation of GABAergic Development with Neurotrophic Factors

神经营养因子对 GABA 能发育的功能和表型调节

基本信息

批准号：
22300107
负责人：
NAWA Hiroyuki
金额：
$ 11.07万
依托单位：
Niigata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

项目摘要

GABAergic neurons play crucial roles in the brain functions, attenuating excitatoryneurotransmission, generating oscillation activity patterns, and regulating developmentalplasticity and critical periods. Recently, we implicate neurotrophic factors of the EGFfamily in the brain diseases of developmental origin such as autism and schizophrenia. Inthe present project, we planed to explore the physiological activity, cellular signaling, and pathologic contribution of EGF-like factors’ actions on GABAergic neurons and theirsubtype(s). Among various subtypes of cortical GABAergic neurons, parvalbumin-positiveGABA neurons carried ErbB4 and reacted with neuregulin-1. This factor elevated theexpression of AMPA-type glutamate receptors, more efficiently derived GABA release, andproduced stronger postsynaptic inhibition. The same type of GABAergic neurons expressedErbB1 and responded to EGF as well, although the direction of the reaction was totallyopposite; EGF down-regulated the glutamate receptor levels and glutamate aciddecarboxylase expression, provoking more modest inhibition in postsynaptic neurons. Incontrast, the same factor, EGF, exerted a distinct action on pallidal GABA neurons; itelevated the excitability of these neurons and enabled those to release more amounts ofGABA in the target region. Therefore, these findings suggest that GABAergic neurons inthe brain harbor dynamic plasticity to react with EGF-like factors but the direction andmagnitude of the phenotypic responses differ significantly depending on individualsubtypes of GABAergic neurons.

gaba能神经元在脑功能、减弱兴奋性神经传递、产生振荡活动模式、调节发育可塑性和关键期等方面发挥着重要作用。最近，我们将egfamily的神经营养因子与发育性脑疾病（如自闭症和精神分裂症）联系起来。在本项目中，我们计划探索egf样因子对gaba能神经元及其亚型的生理活性、细胞信号传导和病理贡献。在皮质gaba能神经元的不同亚型中，parvalbumin阳性的gaba神经元携带ErbB4并与神经调节蛋白1发生反应。该因子提高ampa型谷氨酸受体的表达，更有效地衍生GABA释放，并产生更强的突触后抑制。同样类型的gaba能神经元表达derbb1并对EGF有反应，尽管反应方向完全相反；EGF下调谷氨酸受体水平和谷氨酸酸脱羧酶表达，在突触后神经元中引起更适度的抑制。相反，同样的因子EGF对苍白质GABA神经元有不同的作用；它提高了这些神经元的兴奋性，使它们在目标区域释放更多的gaba。因此，这些研究结果表明，脑内gaba能神经元具有与egf样因子反应的动态可塑性，但表型反应的方向和幅度因gaba能神经元的个体亚型而有显著差异。