Muscleblind1, but Not Dmpk or Six5, Contributes to a Complex Phenotype of Muscular and Motivational Deficits in Mouse Models of Myotonic Dystrophy
Muscleblind1, but Not Dmpk or Six5, Contributes to a Complex Phenotype of Muscular and Motivational Deficits in Mouse Models of Myotonic Dystrophy
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DOI：
10.1371/journal.pone.0009857
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发表时间：
2010-03-25
期刊：
影响因子：
3.7
通讯作者：
Reddy, Sita
中科院分区：
文献类型：
--
作者：
Matynia, Anna;Ng, Carina Hoi;Reddy, Sita
评估分子缺陷的基础上观察到的认知缺陷孟德尔疾病提供了一个独特的机会，以确定人类认知的关键调节。先天性强直性肌营养不良1（cDM 1）是一种多系统疾病，其特征在于认知缺陷和一系列行为异常，包括视觉空间记忆缺陷、焦虑和冷漠。DMPK（肌张力障碍性肌强直蛋白激酶）、SIX5（一种转录因子）或MBNL1（一种RNA剪接调节因子）的水平降低已被证明有助于cDM 1的独特特征。因此，研究了Dmpk、Six5或Mbnl1失活的小鼠品系，以确定每个基因对这些认知功能的相对贡献。开放领域和高架十字迷宫任务被用来检查焦虑，蔗糖消耗被用来评估动机，而水迷宫和上下文恐惧条件被用来检查空间学习和记忆。仅在Mbnl1缺陷小鼠中观察到认知和行为异常，其表现出与Morris水迷宫（一种复杂的视觉空间任务）和用于快感缺乏的蔗糖消耗测试中的动机缺陷一致的行为。所有三种cDM1模型都表现出正常的空间学习和记忆。这些数据确定MBNL1作为情绪状态的潜在调节剂，MBNL1水平降低是在cDM 1中观察到的动机缺陷的基础。
Assessment of molecular defects that underlie cognitive deficits observed in mendelian disorders provides a unique opportunity to identify key regulators of human cognition. Congenital Myotonic Dystrophy 1 (cDM1), a multi-system disorder is characterized by both cognitive deficits and a spectrum of behavioral abnormalities, which include visuo-spatial memory deficits, anxiety and apathy. Decreased levels of DMPK (Dystrophia Myotonica-protein kinase), SIX5, a transcription factor or MBNL1 (Muscleblind-like 1), an RNA splice regulator have been demonstrated to contribute to distinct features of cDM1. Mouse strains in which either Dmpk, Six5 or Mbnl1 are inactivated were therefore studied to determine the relative contribution of each gene to these cognitive functions. The open field and elevated plus maze tasks were used to examine anxiety, sucrose consumption was used to assess motivation, whereas the water maze and context fear conditioning were used to examine spatial learning and memory. Cognitive and behavioral abnormalities were observed only in Mbnl1 deficient mice, which demonstrate behavior consistent with motivational deficits in the Morris water maze, a complex visuo-spatial task and in the sucrose consumption test for anhedonia. All three models of cDM1 exhibit normal spatial learning and memory. These data identify MBNL1 as a potential regulator of emotional state with decreased MBNL1 levels underlying the motivational deficits observed in cDM1.