Over-expression of a human chromosome 22q11.2 segment including TXNRD2, COMT and ARVCF developmentally affects incentive learning and working memory in mice.
Over-expression of a human chromosome 22q11.2 segment including TXNRD2, COMT and ARVCF developmentally affects incentive learning and working memory in mice.
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DOI：
10.1093/hmg/ddp334
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发表时间：
2009-10
影响因子：
3.5
通讯作者：
Go Suzuki;Kathryn M. Harper;T. Hiramoto;B. Funke;Moonsook Lee;Gina Kang;Mahálah R. Buell;M. Geyer;R. Kucherlapati;B. Morrow;P. Männistö;S. Agatsuma;N. Hiroi
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文献类型：
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作者：
Go Suzuki;Kathryn M. Harper;T. Hiramoto;B. Funke;Moonsook Lee;Gina Kang;Mahálah R. Buell;M. Geyer;R. Kucherlapati;B. Morrow;P. Männistö;S. Agatsuma;N. Hiroi
人类染色体22q11.2的复制与智力迟钝、自闭症和许多其他行为表型的发生率升高有关。然而，由于重复覆盖1.5-6 Mb，22q11.2片段因果影响人类行为的精确方式尚不清楚。我们现在已经确定了人类22q11.2的约190 kb片段的过度表达对细菌人工染色体（BAC）转基因（TG）小鼠行为的发育影响，该片段包括基因TXNRD 2、COMT和ARVCF。在1月龄和2月龄时测试BAC TG小鼠和野生型（WT）小鼠的认知能力、情感和压力相关行为以及运动活动。酶法测定BAC过表达对COMT活性水平的影响。BAC TG小鼠更快地接近奖励目标（即激励学习），但在发育过程中延迟奖励交替受损。相比之下，BAC TG和WT小鼠在无延迟的奖励交替，自发交替，前脉冲抑制，社会互动，焦虑，压力和恐惧相关的行为和运动活动中没有区别。与WT小鼠相比，BAC TG小鼠在前额叶皮层、纹状体和海马中的COMT活性水平高出约2倍。这些数据表明，22q11.2片段的过度表达增强了激励性学习，损害了工作记忆的长期维持，但对工作记忆本身、影响和压力相关行为或运动能力没有明显影响。这个22q11.2片段的高拷贝数可能有助于在发育过程中学习和认知的一组高度选择性的表型。
Duplication of human chromosome 22q11.2 is associated with elevated rates of mental retardation, autism and many other behavioral phenotypes. However, because duplications cover 1.5-6 Mb, the precise manner in which segments of 22q11.2 causally affect behavior is not known in humans. We have now determined the developmental impact of over-expression of an approximately 190 kb segment of human 22q11.2, which includes the genes TXNRD2, COMT and ARVCF, on behaviors in bacterial artificial chromosome (BAC) transgenic (TG) mice. BAC TG mice and wild-type (WT) mice were tested for their cognitive capacities, affect- and stress-related behaviors and motor activity at 1 and 2 months of age. An enzymatic assay determined the impact of BAC over-expression on the activity level of COMT. BAC TG mice approached a rewarded goal faster (i.e. incentive learning), but were impaired in delayed rewarded alternation during development. In contrast, BAC TG and WT mice were indistinguishable in rewarded alternation without delays, spontaneous alternation, prepulse inhibition, social interaction, anxiety-, stress- and fear-related behaviors and motor activity. Compared with WT mice, BAC TG mice had an approximately 2-fold higher level of COMT activity in the prefrontal cortex, striatum and hippocampus. These data suggest that over-expression of this 22q11.2 segment enhances incentive learning and impairs the prolonged maintenance of working memory, but has no apparent effect on working memory per se, affect- and stress-related behaviors or motor capacity. High copy numbers of this 22q11.2 segment might contribute to a highly selective set of phenotypes in learning and cognition during development.