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Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):E6420-E6426. doi: 10.1073/pnas.1707661114. Epub 2017 Jul 10.

Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury.

Author information

1
Brain and Spinal Injury Center, University of California, San Francisco, CA 94143.
2
Neuroscience Graduate Program, University of California, San Francisco, CA 94143.
3
Department of Physical Therapy Rehabilitation Science, University of California, San Francisco, CA 94143.
4
Department of Neurological Surgery, University of California, San Francisco, CA 94143.
5
Department of Neuroscience, Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030.
6
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143; peter@walterlab.ucsf.edu Susanna.Rosi@ucsf.edu.
7
Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
8
Brain and Spinal Injury Center, University of California, San Francisco, CA 94143; peter@walterlab.ucsf.edu Susanna.Rosi@ucsf.edu.

Abstract

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability, yet the mechanisms underlying the chronic cognitive deficits associated with TBI remain unknown. Consequently, there are no effective treatments for patients suffering from the long-lasting symptoms of TBI. Here, we show that TBI persistently activates the integrated stress response (ISR), a universal intracellular signaling pathway that responds to a variety of cellular conditions and regulates protein translation via phosphorylation of the translation initiation factor eIF2α. Treatment with ISRIB, a potent drug-like small-molecule inhibitor of the ISR, reversed the hippocampal-dependent cognitive deficits induced by TBI in two different injury mouse models-focal contusion and diffuse concussive injury. Surprisingly, ISRIB corrected TBI-induced memory deficits when administered weeks after the initial injury and maintained cognitive improvement after treatment was terminated. At the physiological level, TBI suppressed long-term potentiation in the hippocampus, which was fully restored with ISRIB treatment. Our results indicate that ISR inhibition at time points late after injury can reverse memory deficits associated with TBI. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat head trauma-induced chronic cognitive deficits.

KEYWORDS:

brain trauma; eIF2α; hippocampus; memory deficits; translational control

PMID:
28696288
PMCID:
PMC5547647
DOI:
10.1073/pnas.1707661114
[Indexed for MEDLINE]
Free PMC Article

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