The integrated stress response in cognitive disorders

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ABSTRACT Cognitive disorders pose a major threat to public health, and represent an enormous economic and social burden. Despite the high incidence of these disorders, effective treatments remain severely limited. Thus, the development of novel therapeutic to treat cognitive disorders is an important goal. Here we focus on the integrated stress response (ISR), a conserved signaling network that restores protein homeostasis by regulating protein synthesis, and a main causative pathway underlying the memory deficits associated with a wide range of cognitive disorders. The goal of this competing renewal is to define the precise molecular, cellular, and circuit mechanisms by which activation of the ISR leads to cognitive dysfunction. In Aim 1, we will generate and characterize mice carrying a human mutation in a key component of the ISR, which activates the ISR, and is associated with intellectual disability. In Aim 2, we will generate and use state-of-the-art, novel molecular- genetic approaches to identify the specific cell types in the brain driving the long-term memory deficits upon activation of the ISR. Finally, in Aim 3, we will develop a novel high-throughput screening platform to identify new inhibitors of the ISR. The results of these Aims will provide new fundamental insights into the biological basis of cognitive dysfunction and hold the hope of opening new therapeutic avenues for cognitive disorders resulting from perturbation of protein homeostasis.