NMDA receptors mediate olfactory learning and memory in Drosophila
NMDA receptors mediate olfactory learning and memory in Drosophila
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DOI：
10.1016/j.cub.2005.02.059
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发表时间：
2005-04-12
期刊：
影响因子：
9.2
通讯作者：
Chiang, AS
中科院分区：
文献类型：
--
作者：
Xia, SZ;Miyashita, T;Chiang, AS
背景资料：NMDARs的分子和电生理特性表明，它们可能是Hebbian的“巧合探测器”，假设为联想学习的基础。然而，由于调节NMDAR功能的药物的非特异性或来自哺乳动物研究的各种NMDAR亚基的相对慢性的遗传操作，缺乏NMDAR在成人行为可塑性中的急性作用的确凿证据。此外，NMDARs在记忆巩固中的作用仍然存在争议。结果：果蝇基因组编码两个NMDAR同源物，dNR 1和dNR 2。当在非洲爪蟾卵母细胞或果蝇S2细胞中共表达时，dNR 1和dNR 2形成具有脊椎动物NMDAR观察到的几种不同分子特性的功能性NMDAR，包括谷氨酸盐的电压/Mg 2+依赖性激活。这两种蛋白质在整个大脑中都有弱表达，但在蘑菇体树突区域周围的几个神经元中表现出优先表达。基本dNR 1基因的亚型突变破坏嗅觉学习，这种学习缺陷被野生型转基因挽救。重要的是，我们表明，巴甫洛夫学习中断后15小时内瞬时诱导的dNR 1反义RNA转基因的成年人。扩展训练足以克服这种初始学习缺陷，但在这些训练条件下，长期记忆（LTM）会被消除。我们的研究使用了分子遗传学工具的组合，以（1）产生dNR 1基因的基因组突变，（2）用dNR 1（+）转基因挽救伴随的学习缺陷，和（3）快速和瞬时地敲低成年人中的dNR 1（+）表达，从而证明NMDAR急性参与联合学习和记忆的进化保守作用。
Background: Molecular and electrophysiological properties of NMDARs suggest that they may be the Hebbian "coincidence detectors" hypothesized to underlie associative learning. Because of the nonspecificity of drugs that modulate NMDAR function or the relatively chronic genetic manipulations of various NMDAR subunits from mammalian studies, conclusive evidence for such an acute role for NMDARs in adult behavioral plasticity, however, is lacking. Moreover, a role for NMDARs in memory consolidation remains controversial.Results: The Drosophila genome encodes two NMDAR homologs, dNR1 and dNR2. When coexpressed in Xenopus oocytes or Drosophila S2 cells, dNR1 and dNR2 form functional NMDARs with several of the distinguishing molecular properties observed for vertebrate NMDARs, including voltage/Mg2+-dependent activation by glutamate. Both proteins are weakly expressed throughout the entire brain but show preferential expression in several neurons surrounding the dendritic region of the mushroom bodies. Hypomorphic mutations of the essential dNR1 gene disrupt olfactory learning, and this learning defect is rescued with wildtype transgenes. Importantly, we show that Pavlovian learning is disrupted in adults within 15 hr after transient induction of a dNR1 antisense RNA transgene. Extended training is sufficient to overcome this initial learning defect, but long-term memory (LTM) specifically is abolished under these training conditions.Conclusions: Our study uses a combination of molecular-genetic tools to (1) generate genomic mutations of the dNR1 gene, (2) rescue the accompanying learning deficit with a dNR1(+) transgene, and (3) rapidly and transiently knockdown dNR1(+) expression in adults, thereby demonstrating an evolutionarily conserved role for the acute involvement of NMDARs in associative learning and memory.