Grue, K. | bioRxiv Science

bioRxiv2022

Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition.

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability in the world and the strongest environmental risk factor for the development of dementia. Even mild TBI (resulting from concussive injuries) is associated with a >2-fold increase in the risk of dementia onset. Little is known about the cellular mechanisms responsible for the progression of long lasting cognitive deficits. The integrated stress response (ISR), a phylogenetically conserved pathway involved in the cellular response to stress, is activated after TBI, axsnd inhibition of the ISR -- even weeks after injury -- can reverse behavioral and cognitive deficits. However, the cellular mechanisms by which ISR inhibition restores cognition are unknown. Here we used longitudinal two-photon imaging in vivo after concussive injury in mice to study dendritic spine dynamics in the parietal cortex, a brain region involved in working memory. Concussive injury profoundly altered spine dynamics measured up to a month after injury. Strikingly, brief pharmacological treatment with the drug-like small-molecule ISR inhibitor ISRIB entirely reversed the structural changes measured in the parietal cortex and the associated working memory deficits. Thus, both neural and cognitive consequences of concussive injury are mediated in part by activation of the ISR and can be corrected by its inhibition. These findings suggest that targeting ISR activation could serve as a promising approach for the clinical treatment of chronic cognitive deficits after TBI. Significance StatementAfter traumatic brain injury, temporary pharmacological inhibition of the integrated stress response (ISR), with a small-molecule inhibitor (ISRIB), rescued long lasting trauma-induced cognitive deficits. Here, we found that ISRIB treatment rapidly and persistently reversed the aberrant changes in cortical spine dynamics in the parietal cortex while rescuing working memory deficits. These data suggests that the link between the ISR and memory function involves, at least in part, changes in neuronal structure. Targeting ISR activation could serve as a promising approach for the clinical treatment of chronic cognitive deficits after brain injuries.

neuroscience↗

bioRxiv2020

Small molecule cognitive enhancer reverses age-related memory decline in mice.

With increased life expectancy age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition i) rescues intrinsic neuronal electrophysiological properties, ii) restores spine density and iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals. ONE SENTENCE SUMMARYInhibition of the integrated stress response restores neuronal and immune dysfunction and alleviates memory deficits in aged mice.

neuroscience↗