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Mechanisms underlying action of neurotrophic factors on postsynaptic glutamate and GABA receptors

神经营养因子对突触后谷氨酸和 GABA 受体作用的机制

基本信息

批准号：
14208094
负责人：
TSUMOTO Tadaharu
金额：
$ 34.86万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Previously we found that brain-derived neurotrophic factor (BDNF) is released from presynaptic sites in an activity-dependent manner and acts on postsynaptic neurons. In this study we attempted to see whether actions of BDNF are different between glutamatergic excitatory synapses and GABAergic inhibitory synapses, and further to elucidate mechanisms underlying such actions. We obtained the following results.1.Using mixed neuron culture preparations obtained from green fluorescence protein (GFP) mice and BDNF knockout mice, we explored what actions presynaptic BDNF exerts on postsynaptic neurons. We found that presynaptic BDNF promotes dendritic development of postsynaptic GABAergic neurons.2.Actions of exogenous BDNF on GABAergic synapses were investigated in solitary GABAergic neurons cultured on glial microisland to completely exclude possible involvement of excitatory synapses from the observed effects of BDNF. We found that BDNF increased the number of active GABAergic synapses.3.Roles of endogenous BDNF in development of glutamatergic synapses were investigated in barrel cortex of BDNF knockout and wild type mice. We found that silent synapses, which consist only of NMDA receptors, are abnormally increased in BDNF knockout mice, and this is rescued by exogenously applied BDNF.4.Actions of exogenous BDNF on excitatory synapses on GABAergic neurons were not studied previously. We addressed this issue by using GAD67-GFP knock-in mice, in which GABAergic neurons are easily identified. We found that BDNF acutely depressed function of excitatory synapses to GABAergic neurons.

以前我们发现脑源性神经营养因子（BDNF）以活动依赖的方式从突触前部位释放并作用于突触后神经元。在本研究中，我们试图了解BDNF的作用是否在海马能兴奋性突触和GABA能抑制性突触之间存在差异，并进一步阐明这种作用的机制。主要结果如下：1.利用绿色荧光蛋白（GFP）小鼠和BDNF基因敲除小鼠的神经元混合培养物，探讨了突触前BDNF对突触后神经元的作用。我们发现突触前BDNF促进突触后GABA能神经元的树突发育。2.在胶质细胞微岛上培养的GABA能神经元上研究了外源性BDNF对GABA能突触的作用，以完全排除BDNF对兴奋性突触的影响。我们发现BDNF可增加活跃的GABA能突触的数量。3.在BDNF基因敲除小鼠和野生型小鼠的桶状皮质中研究内源性BDNF在GABA能突触发育中的作用。我们发现BDNF基因敲除小鼠的沉默突触（只由NMDA受体组成）异常增加，而外源性BDNF的应用可以挽救这种沉默突触。4.外源性BDNF对GABA能神经元兴奋性突触的作用以前没有研究过。我们通过使用GAD 67-GFP基因敲入小鼠解决了这个问题，其中GABA能神经元很容易识别。我们发现BDNF能急性抑制GABA能神经元兴奋性突触的功能。