Impairment of spatial memory accuracy improved by Cbr1 copy number resumption and GABAB receptor-dependent enhancement of synaptic inhibition in Down syndrome model mice
Impairment of spatial memory accuracy improved by Cbr1 copy number resumption and GABAB receptor-dependent enhancement of synaptic inhibition in Down syndrome model mice
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DOI：
10.1038/s41598-020-71085-9
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发表时间：
2020-08-25
影响因子：
4.6
通讯作者：
Manabe, Toshiya
中科院分区：
文献类型：
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作者：
Arima-Yoshida, Fumiko;Raveau, Matthieu;Manabe, Toshiya
唐氏综合症是一种复杂的遗传疾病，由人类21号染色体的三个拷贝引起。最常见的模型是Ts2Cje、Ts1Cje和Ts1Rhr小鼠，它们携带与人类21号染色体相同的小鼠16号染色体重叠片段的额外拷贝。通过对海马切片的电生理分析，我们发现Ts1Cje和Ts2Cje小鼠在受到GABA(B)受体调控的强电刺激时的去极化后期明显小于WT对照组，而Ts1Rhr小鼠则没有。此外，分离的GABA(B)受体介导的抑制性突触反应在Ts1Cje小鼠中更大。据我们所知，这是第一个直接显示GABA(B)受体介导的突触电流在Ts1Cje小鼠中增强的报告。这些结果表明，GABA(B)受体介导的突触抑制在Ts1Cje和Ts2Cje小鼠中增强，而在Ts1Rhr小鼠中没有增强。Cbr1基因在Ts1Cje和Ts2Cje中有三个拷贝，但在Ts1Rhr中没有，它编码羰基还原酶，通过减少前列腺素E2 （PGE2）来促进GABA(B)受体的活性。有趣的是，我们发现，当仅将Cbr1设置为两个拷贝（Ts1Cje;Cbr1(+/+/-)）时，Ts1Cje小鼠的PGE2减少和记忆障碍得到缓解。然而，在Ts1Cje中，GABA(B)受体依赖性的突触抑制增强在Ts1Cje中没有改变；Cbr1(+ / + / -)老鼠。这些结果表明，Cbr1是导致DS认知障碍的基因之一，而在Ts1Rhr中不包含Cbr1的基因是GABA(B)受体依赖性过度抑制的基因。
Down syndrome is a complex genetic disorder caused by the presence of three copies of the chromosome 21 in humans. The most common models, carrying extra-copies of overlapping fragments of mouse chromosome 16 that is syntenic to human chromosome 21, are Ts2Cje, Ts1Cje and Ts1Rhr mice. In electrophysiological analyses using hippocampal slices, we found that the later phase of the depolarization during tetanic stimulation, which was regulated by GABA(B) receptors, was significantly smaller in Ts1Cje and Ts2Cje mice than that in WT controls but not in Ts1Rhr mice. Furthermore, isolated GABA(B) receptor-mediated inhibitory synaptic responses were larger in Ts1Cje mice. To our knowledge, this is the first report that directly shows the enhancement of GABA(B) receptor-mediated synaptic currents in Ts1Cje mice. These results suggest that GABA(B) receptor-mediated synaptic inhibition was enhanced in Ts1Cje and Ts2Cje mice but not in Ts1Rhr mice. The Cbr1 gene, which is present in three copies in Ts1Cje and Ts2Cje but not in Ts1Rhr, encodes carbonyl reductase that may facilitate GABA(B)-receptor activity through a reduction of prostaglandin E2 (PGE2). Interestingly, we found that a reduction of PGE2 and an memory impairment in Ts1Cje mice were alleviated when only Cbr1 was set back to two copies (Ts1Cje;Cbr1(+/+/-)). However, the GABA(B) receptor-dependent enhancement of synaptic inhibition in Ts1Cje was unaltered in Ts1Cje;Cbr1(+/+/-) mice. These results indicate that Cbr1 is one of the genes responsible for DS cognitive impairments and the gene(s) other than Cbr1, which is included in Ts1Cje but not in Ts1Rhr, is responsible for the GABA(B) receptor-dependent over-inhibition.