Traumatic brain injury (TBI) is a leading cause of long-term neurological disability and affects an ever-growing population. Currently, there are no effective treatments for patients suffering from chronic TBI-induced cognitive impairments. Here, we found that suppression of the integrated stress response (ISR) with a drug-like small-molecule inhibitor, ISRIB, rescued cognition in two TBI mouse models, even when administered weeks after injury. Consistent with the behavioral results, ISRIB restored long-term potentiation deficits observed in TBI mice. Our data suggest that targeting ISR activation could serve as a promising approach for the treatment of chronic cognitive dysfunction after TBI.

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.