Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility

Mimi A. Trinh, Hanoch Kaphzan, Ronald Wek, Philippe Pierre, Douglas R. Cavener, Eric Klann

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)676-688
Number of pages13
JournalCell Reports
Volume1
Issue number6
DOIs
StatePublished - Jun 28 2012

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Brain
Phosphotransferases
Phosphorylation
Cognition
Schizophrenia
Glycine Plasma Membrane Transport Proteins
Frontal Lobe
Prosencephalon
Prefrontal Cortex
Nervous System Diseases
Automatic Data Processing
Fear
Modulation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility. / Trinh, Mimi A.; Kaphzan, Hanoch; Wek, Ronald; Pierre, Philippe; Cavener, Douglas R.; Klann, Eric.

In: Cell Reports, Vol. 1, No. 6, 28.06.2012, p. 676-688.

Research output: Contribution to journalArticle

Trinh, Mimi A. ; Kaphzan, Hanoch ; Wek, Ronald ; Pierre, Philippe ; Cavener, Douglas R. ; Klann, Eric. / Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility. In: Cell Reports. 2012 ; Vol. 1, No. 6. pp. 676-688.
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