Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility
Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility
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DOI：
10.1016/j.celrep.2012.04.010
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发表时间：
2012-06-01
期刊：
影响因子：
8.8
通讯作者：
Klann, Eric
中科院分区：
文献类型：
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作者：
Trinh, Mimi A.;Kaphzan, Hanoch;Klann, Eric
翻译控制依赖于PKR样ER激酶（PERK）对eIF2 α的磷酸化。为了研究PERK在认知功能中的作用，我们选择性地破坏PERK在成年小鼠前脑中的表达。在PERK缺陷小鼠的前额叶皮层（PFC）中，eIF2 α磷酸化和ATF 4表达减少，并与增强的行为持续，减少前脉冲抑制，减少恐惧消退和受损的行为灵活性相关。用甘氨酸转运蛋白抑制剂SSR504734治疗使PERK缺陷小鼠的eIF2 α磷酸化、ATF 4表达和行为灵活性正常化。此外，PERK和ATF4的表达水平在精神分裂症患者的额叶皮层中降低。总之，我们的研究结果表明，PERK在信息处理和认知功能中起着关键作用，并且调节eIF2 α磷酸化和ATF4表达可能是治疗与精神分裂症等几种神经系统疾病相关的行为障碍的有效策略。
Translational control depends on phosphorylation of eIF2 alpha by PKR-like ER kinase (PERK). To examine the role of PERK in cognitive function, we selectively disrupted PERK expression in the adult mouse fore-brain. In the prefrontal cortex (PFC) of PERK-deficient mice, eIF2 alpha phosphorylation and ATF4 expression were diminished and were associated with enhanced behavioral perseveration, decreased prepulse inhibition, reduced fear extinction, and impaired behavioral flexibility. Treatment with the glycine transporter inhibitor SSR504734 normalized eIF2 alpha phosphorylation, ATF4 expression, and behavioral flexibility in PERK-deficient mice. Moreover, the expression levels of PERK and ATF4 were reduced in the frontal cortex of human patients with schizophrenia. Together, our findings reveal that PERK plays a critical role in information processing and cognitive function and that modulation of eIF2 alpha phosphorylation and ATF4 expression may represent an effective strategy for treating behavioral inflexibility associated with several neurological disorders such as schizophrenia.