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首页> 外文期刊>The European Journal of Neuroscience >Down-regulation of protocadherin-alpha A isoforms in mice changes contextual fear conditioning and spatial working memory.
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Down-regulation of protocadherin-alpha A isoforms in mice changes contextual fear conditioning and spatial working memory.

机译：小鼠中原钙粘蛋白-αA亚型的下调会改变背景恐惧条件和空间工作记忆。

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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(DeltaBneo/DeltaBneo) 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(DeltaAneo/DeltaAneo) mice, which lacked 57 amino acids of the Pcdh-alpha A cytoplasmic tail. These learning abnormalities were, however, not seen in Pcdh-alpha(DeltaB/DeltaB) mice [in which the neomycin-resistance (neo) gene cassette was removed from the Pcdh-alpha(DeltaBneo/DeltaBneo) 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(DeltaB/DeltaB). 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.
机译：在基因组中被编码为大簇（由α，β和γ簇组成）的各种原钙粘蛋白（Pcdhs）定位于轴突和突触。已经提出，Pcdhs有助于复杂的神经网络的产生并调节脑功能。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蛋白的基因敲除小鼠，并检查了它们的行为异常。 Pcdh-alpha恒定区有两个可变的剪接变体，Pcdh-alpha A和B同种型，具有不同的胞质尾巴。 Pcdh-alpha（DeltaBneo / DeltaBneo）小鼠，其中不存在Pcdh-alpha B剪接变体，而Pcdh-alpha A亚型下调至野生型水平的大约20％，表现出增强的情境恐惧调节和差异在八臂径向迷宫中。在缺少Pcdh-alpha A细胞质尾巴的57个氨基酸的Pcdh-alpha（DeltaAneo / DeltaAneo）小鼠中发现了类似的异常。但是，在Pcdh-alpha（DeltaB / DeltaB）小鼠中没有发现这些学习异常[其中从Pcdh-alpha（DeltaBneo / DeltaBneo）等位基因中删除了新霉素抗性（neo）基因盒]，其中尽管大脑中仍完全缺少Pcdh-alpha B的同工型，但Pcdh-alpha A的同工型的水平得以恢复。此外，亚型Pcdh-alpha A突变小鼠海马中5-羟色胺的含量增加，但恢复Pcdh-alpha（DeltaB / DeltaB）却没有。这些结果表明，大脑中Pcdh-alpha A同工型的水平在调节学习和记忆功能以及海马中5-羟色胺的含量方面具有重要作用。

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