Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility
Translational control depends on phosphorylation of eIF2α by PKR-like ER kinase (PERK). To examine the role of PERK in cognitive function, we selectively disrupted PERK expression in the adult mouse forebrain. In the prefrontal cortex (PFC) of PERK-deficient mice, eIF2α phosphorylation and ATF4 expr...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2012-06-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124712001234 |
| _version_ | 1811314458706837504 |
|---|---|
| author | Mimi A. Trinh Hanoch Kaphzan Ronald C. Wek Philippe Pierre Douglas R. Cavener Eric Klann |
| author_facet | Mimi A. Trinh Hanoch Kaphzan Ronald C. Wek Philippe Pierre Douglas R. Cavener Eric Klann |
| author_sort | Mimi A. Trinh |
| collection | DOAJ |
| description | Translational control depends on phosphorylation of eIF2α by PKR-like ER kinase (PERK). To examine the role of PERK in cognitive function, we selectively disrupted PERK expression in the adult mouse forebrain. In the prefrontal cortex (PFC) of PERK-deficient mice, eIF2α 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 eIF2α 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 eIF2α phosphorylation and ATF4 expression may represent an effective strategy for treating behavioral inflexibility associated with several neurological disorders such as schizophrenia. |
| first_indexed | 2024-04-13T11:11:57Z |
| format | Article |
| id | doaj.art-4072491586314068aff23161f4c9f3e0 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-13T11:11:57Z |
| publishDate | 2012-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-4072491586314068aff23161f4c9f3e02022-12-22T02:49:05ZengElsevierCell Reports2211-12472012-06-011667668810.1016/j.celrep.2012.04.010Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral FlexibilityMimi A. Trinh0Hanoch Kaphzan1Ronald C. Wek2Philippe Pierre3Douglas R. Cavener4Eric Klann5Center for Neural Science, New York University, New York, NY 10003, USACenter for Neural Science, New York University, New York, NY 10003, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USACentre d'Immunologie de Marseille-Luminy, Unité Mixte de Recherche 6102, Centre National de la Recherche Scientifique, Université de la Méditerranée, Case 906, 13288 Marseille, FranceDepartment of Biology, University Park, Pennsylvania State University, University Park, PA 16802, USACenter for Neural Science, New York University, New York, NY 10003, USATranslational control depends on phosphorylation of eIF2α by PKR-like ER kinase (PERK). To examine the role of PERK in cognitive function, we selectively disrupted PERK expression in the adult mouse forebrain. In the prefrontal cortex (PFC) of PERK-deficient mice, eIF2α 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 eIF2α 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 eIF2α phosphorylation and ATF4 expression may represent an effective strategy for treating behavioral inflexibility associated with several neurological disorders such as schizophrenia.http://www.sciencedirect.com/science/article/pii/S2211124712001234 |
| spellingShingle | Mimi A. Trinh Hanoch Kaphzan Ronald C. Wek Philippe Pierre Douglas R. Cavener Eric Klann Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility Cell Reports |
| title | Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility |
| title_full | Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility |
| title_fullStr | Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility |
| title_full_unstemmed | Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility |
| title_short | Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility |
| title_sort | brain specific disruption of the eif2α kinase perk decreases atf4 expression and impairs behavioral flexibility |
| url | http://www.sciencedirect.com/science/article/pii/S2211124712001234 |
| work_keys_str_mv | AT mimiatrinh brainspecificdisruptionoftheeif2akinaseperkdecreasesatf4expressionandimpairsbehavioralflexibility AT hanochkaphzan brainspecificdisruptionoftheeif2akinaseperkdecreasesatf4expressionandimpairsbehavioralflexibility AT ronaldcwek brainspecificdisruptionoftheeif2akinaseperkdecreasesatf4expressionandimpairsbehavioralflexibility AT philippepierre brainspecificdisruptionoftheeif2akinaseperkdecreasesatf4expressionandimpairsbehavioralflexibility AT douglasrcavener brainspecificdisruptionoftheeif2akinaseperkdecreasesatf4expressionandimpairsbehavioralflexibility AT ericklann brainspecificdisruptionoftheeif2akinaseperkdecreasesatf4expressionandimpairsbehavioralflexibility |