Project 462252

Long-term memory can be enhanced by suppressing the evolutionary conserved intracellular signaling pathway, Integrated Stress Response (ISR). The ISR allows cells to cope with distinct cellular stresses by modulating the production of new proteins. Suppression of the ISR via genetic or pharmacological manipulations enhances long-lasting memory in healthy mice and corrects memory deficits in animal models of Alzheimer's disease. Despite significant progress in understanding the underlying mechanisms by which the ISR controls cognitive functions, several key questions remain unanswered. The role of the ISR in astrocytes, non-neuronal cells that are implicated in cognitive processes, is unknown. Moreover, the mechanisms linking neuronal activity to suppression of the ISR are not well understood. In this proposal, we will address these fundamental questions using a combination of advanced genetic mouse models, cell-type-specific biochemistry, behavioral and electrophysiological approaches. The knowledge obtained in this work will expand the understanding of basic mechanisms by which manipulation of the ISR promotes cognition. Most importantly, it has the potential to facilitate and refine the implementation of strategies based on ISR modulation in the treatment of diseases associated with memory loss such as Alzheimer's disease and dementia.