Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1
Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1
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DOI：
10.1073/pnas.1016424108
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发表时间：
2011-01-25
影响因子：
11.1
通讯作者：
Watanabe, Yoshifumi
中科院分区：
文献类型：
--
作者：
Uchida, Shusaku;Hara, Kumiko;Watanabe, Yoshifumi
脑中的异常转录调节被认为是神经精神疾病的发病机制和病理生理学的关键组成部分之一。热休克因子（HSFs）通过调控基因表达来调节细胞内稳态。然而，HSFs在脑功能中的作用尚未完全阐明。在本研究中，我们试图阐明HSF 1介导的基因调控的作用，在神经元和行为的发展，使用HSF 1缺陷（HSF 1（-/-））小鼠。我们在HSF 1（-/-）小鼠的齿状回中发现了形态异常的颗粒神经元和受损的神经发生。此外，HSF 1（-/-）小鼠表现出异常的情感行为，包括焦虑和社交能力降低，但抑郁样行为和攻击性增加。此外，HSF 1缺乏增强了重复暴露于约束压力的行为脆弱性。重要的是，拯救新生儿而不是成年海马体中的HSF 1缺陷逆转了异常的焦虑和抑郁样行为。这些结果表明海马HSF 1在神经元和行为发育中起着至关重要的作用。分子机制的分析表明，HSF 1直接调节聚唾液酸转移酶基因的表达，然后调节海马中聚唾液酸-神经细胞粘附分子（PSA-NCAM）的水平。从新生儿海马中酶促去除PSA导致成年期的异常行为，与在HSF 1（-/-）小鼠中观察到的相似。因此，这些结果表明，HSF 1的作用之一是通过多聚唾液酸转移酶的转录调节来控制海马PSA-NCAM水平，这一过程可能涉及小鼠的神经元和行为发育。
Aberrant transcriptional regulation in the brain is thought to be one of the key components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Heat shock factors (HSFs) modulate cellular homeostasis through the control of gene expression. However, the roles of HSFs in brain function have yet to be elucidated fully. In the present study, we attempted to clarify the role of HSF1-mediated gene regulation in neuronal and behavioral development using HSF1-deficient (HSF1(-/-)) mice. We found granule neurons of aberrant morphology and impaired neurogenesis in the dentate gyrus of HSF1(-/-) mice. In addition, HSF1(-/-) mice showed aberrant affective behavior, including reduced anxiety and sociability but increased depression-like behavior and aggression. Furthermore, HSF1 deficiency enhanced behavioral vulnerability to repeated exposure to restraint stress. Importantly, rescuing the HSF1 deficiency in the neonatal but not the adult hippocampus reversed the aberrant anxiety and depression-like behaviors. These results indicate a crucial role for hippocampal HSF1 in neuronal and behavioral development. Analysis of the molecular mechanisms revealed that HSF1 directly modulates the expression of polysialyltransferase genes, which then modulate polysialic acid-neural cell adhesion molecule (PSA-NCAM) levels in the hippocampus. Enzymatic removal of PSA from the neonatal hippocampus resulted in aberrant behavior during adulthood, similar to that observed in HSF1(-/-) mice. Thus, these results suggest that one role of HSF1 is to control hippocampal PSA-NCAM levels through the transcriptional regulation of polysialyltransferases, a process that might be involved in neuronal and behavioral development in mice.