Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury
Krukowski K1,2, Chou A1,2, Jopson T1,3, Zhu PJ7, Costa-Mattioli M7, Walter P5,6,*, Rosi S1,2,3,4,*
1Brain and Spinal Injury Center, 2Neuroscience Graduate Program, Departments of 3Physical Therapy Rehabilitation Science, 4Neurological Surgery, 5Biochemistry and Biophysics, University of California at San Francisco, CA, USA, 6Howard Hughes Medical Institute, University of California at San Francisco, CA, USA; 7Department of Neuroscience, Memory and Brain Research Center, Baylor College of Medicine, Houston, Texas, USA
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.