Down-regulation of protocadherin-α A isoforms in mice changes contextual fear conditioning and spatial working memory
Down-regulation of protocadherin-α A isoforms in mice changes contextual fear conditioning and spatial working memory
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DOI：
10.1111/j.1460-9568.2008.06428.x
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发表时间：
2008-10-01
影响因子：
3.4
通讯作者：
Yagi, Takeshi
中科院分区：
文献类型：
--
作者：
Fukuda, Emi;Hamada, Shun;Yagi, Takeshi
在基因组中编码为大簇（由α、β和γ簇组成）的多种原钙粘蛋白（Pcdhs）定位于轴突和突触。Pcdhs被认为有助于生成复杂的神经网络并调节大脑功能。为了解决Pcdhs在调节个体行为中的分子作用，在这里，我们产生了Pcdh-alpha蛋白的敲低小鼠，并检查了它们的行为异常。Pcdh-α恒定区有两种选择性剪接变体，Pcdh-α A和B同种型，具有不同的胞质尾区。Pcdh-α（Delta Bneo/Delta Bneo）小鼠，其中Pcdh-α B剪接变体缺失，Pcdh-α A亚型下调至野生型水平的约20%，在八臂放射状迷宫中表现出增强的情境恐惧条件反射和差异。在Pcdh-α（Delta Aneo/Delta Aneo）小鼠中发现了类似的异常，这些小鼠缺乏Pcdh-α A胞质尾的57个氨基酸。然而，在Pcdh-α（Delta B/Delta B）小鼠[其中新霉素抗性（neo）基因盒从Pcdh-α（Delta Bneo/Delta Bneo）等位基因中去除]中未观察到这些学习异常，其中Pcdh-α A同种型的表达水平恢复，尽管Pcdh-α B同种型在脑中仍然完全缺失。此外，5-羟色胺的量增加，在海马的亚形态Pcdh-α A突变小鼠，但不恢复Pcdh-α（Δ B/Δ B）。这些结果表明，大脑中Pcdh-alpha A亚型的水平对调节学习和记忆功能以及海马中5-羟色胺的含量具有重要作用。
Diverse protocadherins (Pcdhs), which are encoded as a large cluster (composed of alpha, beta and gamma clusters) in the genome, are localized to axons and synapses. The Pcdhs have been proposed to contribute to the generation of sophisticated neural networks and to regulate brain function. To address the molecular roles of Pcdhs in regulating individual behavior, here we generated knockdown mice of Pcdh-alpha proteins and examined their behavioral abnormalities. There are two alternative splicing variants of the Pcdh-alpha constant region, Pcdh-alpha A and B isoforms, with different cytoplasmic tails. Pcdh-alpha(Delta Bneo/Delta Bneo) mice, in which the Pcdh-alpha B splicing variant was absent and the Pcdh-alpha A isoforms were down-regulated to approximately 20% of the wild-type level, exhibited enhanced contextual fear conditioning and disparities in an eight-arm radial maze. Similar abnormalities were found in Pcdh-alpha(Delta Aneo/Delta Aneo) mice, which lacked 57 amino acids of the Pcdh-alpha A cytoplasmic tail. These learning abnormalities were, however, not seen in Pcdh-alpha(Delta B/Delta B) mice [in which the neomycin-resistance (neo) gene cassette was removed from the Pcdh-alpha(Delta Bneo/Delta Bneo) alleles], in which the expression level of the Pcdh-alpha A isoforms was recovered, although the Pcdh-alpha B isoforms were still completely missing in the brain. In addition, the amount of 5-hydroxytryptamine increased in the hippocampus of the hypomorphic Pcdh-alpha A mutant mice but not in recovery Pcdh-alpha(Delta B/Delta B). These results suggested that the level of Pcdh-alpha A isoforms in the brain has an important role in regulating learning and memory functions and the amount of 5-hydroxytryptamine in the hippocampus.