Reduced Expression of the ATRX Gene, a Chromatin-Remodeling Factor, Causes Hippocampal Dysfunction in Mice
Reduced Expression of the ATRX Gene, a Chromatin-Remodeling Factor, Causes Hippocampal Dysfunction in Mice
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DOI：
10.1002/hipo.20782
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发表时间：
2011-06-01
期刊：
影响因子：
3.5
通讯作者：
Kitajima, Isao
中科院分区：
文献类型：
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作者：
Nogami, Tatsuya;Beppu, Hideyuki;Kitajima, Isao
在α-地中海贫血X连锁智力低下(ATR-X)综合征患者中发现了ATRX基因的突变，该基因编码一种依赖于ATP的染色质重塑因子。有一种较轻微的ATR-X综合征变种是由该基因的外显子2突变引起的。为了检测外显子2突变对神经元发育的影响，我们产生了ATRX突变(ATRX(Delta E2))小鼠。ATRX(Delta E2)突变等位基因表达水平降低，产生截短的ATRX蛋白。ATRX(Delta E2)小鼠存活并正常繁殖。野生型和ATRX(Delta E2)小鼠的Morris水迷宫实验结果无显著差异。然而，在情境恐惧条件反射测试中，ATRX(Delta E2)小鼠的总冻结时间比野生型小鼠减少，这表明ATRX(Delta E2)小鼠的情境恐惧记忆受损。ATRX(Delta E2)小鼠表现出由高频刺激引起的海马CA1区长时程增强显著降低。此外，与野生型小鼠相比，ATRX(Delta E2)小鼠海马区钙调素依赖的激酶II(αCaMKII)的自动磷酸化和谷氨酸受体离子型AMPA1(GluR1)的磷酸化水平降低。这些发现表明，ATRX(Delta E2)小鼠可能存在恐惧相关的学习障碍，并伴有αCaMKII和GluR1的功能障碍。ATRX(Delta E2)小鼠将是研究染色质重塑因子在异常行为和学习障碍发病机制中作用的有用工具。(C)2010年Wiley-Liss公司
Mutations of the ATRX gene, which encodes an ATP-dependent chromatin-remodeling factor, were identified in patients with alpha-thalassemia X-linked mental retardation (ATR-X) syndrome. There is a milder variant of ATR-X syndrome caused by mutations in the Exon 2 of the gene. To examine the impact of the Exon 2 mutation on neuronal development, we generated ATRX mutant (ATRX(Delta E2)) mice. Truncated ATRX protein was produced from the ATRX(Delta E2) mutant allele with reduced expression level. The ATRX(Delta E2) mice survived and reproduced normally. There was no significant difference in Morris water maze test between wild-type and ATRX(Delta E2) mice. In a contextual fear conditioning test, however, total freezing time was decreased in ATRX(Delta E2) mice compared to wild-type mice, suggesting that ATRX(Delta E2) mice have impaired contextual fear memory. ATRX(Delta E2) mice showed significantly reduced long-term potentiation in the hippocampal CA1 region evoked by high-frequency stimulation. Moreover, autophosphorylation of calcium-calmodulin-dependent kinase II (alpha CaMKII) and phosphorylation of glutamate receptor, ionotropic, AMPA 1 (GluR1) were decreased in the hippocampi of the ATRX(Delta E2) mice compared to wild-type mice. These findings suggest that ATRX(Delta E2) mice may have fear-associated learning impairment with the dysfunction of alpha CaMKII and GluR1. The ATRX(Delta E2) mice would be useful tools to investigate the role of the chromatin-remodeling factor in the pathogenesis of abnormal behaviors and learning impairment. (C) 2010 Wiley-Liss, Inc.