Institut Curie, Orsay, France ; CNRS UMR3306, Orsay, France ; INSERM U1005, Orsay, France ; University Paris-Sud, Orsay, France.
PLoS One. 2013 Sep 3;8(9):e73902. doi: 10.1371/journal.pone.0073902. eCollection 2013.
Huntington's disease (HD) is a fatal neurodegenerative disease, characterized by motor defects and psychiatric symptoms, including mood disorders such as anxiety and depression. HD is caused by an abnormal polyglutamine (polyQ) expansion in the huntingtin (HTT) protein. The development and analysis of various mouse models that express pathogenic polyQ-HTT revealed a link between mutant HTT and the development of anxio-depressive behaviors and various hippocampal neurogenesis defects. However, it is unclear whether such phenotype is linked to alteration of HTT wild-type function in adults. Here, we report the analysis of a new mouse model in which HTT is inducibly deleted from adult mature cortical and hippocampal neurons using the CreER(T2)/Lox system. These mice present defects in both the survival and the dendritic arborization of hippocampal newborn neurons. Our data suggest that these non-cell autonomous effects are linked to defects in both BDNF transport and release upon HTT silencing in hippocampal neurons, and in BDNF/TrkB signaling. The controlled deletion of HTT also had anxiogenic-like effects. Our results implicate endogenous wild-type HTT in adult hippocampal neurogenesis and in the control of mood disorders.
亨廷顿病（HD）是一种致命的神经退行性疾病，其特征为运动缺陷和精神症状，包括焦虑和抑郁等情绪障碍。HD 是由亨廷顿蛋白（HTT）中的异常多聚谷氨酰胺（polyQ）扩展引起的。表达致病 polyQ-HTT 的各种小鼠模型的发展和分析表明，突变 HTT 与焦虑抑郁行为的发展以及各种海马神经发生缺陷之间存在关联。然而，尚不清楚这种表型是否与成年期 HTT 野生型功能的改变有关。在这里，我们报告了一种新的小鼠模型的分析，该模型使用 CreER(T2)/Lox 系统可在成年成熟的皮质和海马神经元中诱导性地删除 HTT。这些小鼠的海马新生神经元的存活和树突分支都存在缺陷。我们的数据表明，这些非细胞自主效应与 HTT 沉默后 BDNF 的运输和释放缺陷以及 BDNF/TrkB 信号传导有关。HTT 的受控缺失也具有焦虑样作用。我们的结果表明，内源性野生型 HTT 参与了成年海马神经发生和情绪障碍的控制。
