Tuning stress protects cognition Down syndrome (DS) is a chromosomal disorder that occurs when a person has an extra copy of chromosome 21. DS causes intellectual disabilities, among other health issues, but little is known about the mechanisms underlying the memory deficits in DS. Zhu et al. used a multidisciplinary approach to show that a defect in integrated stress response, a conserved pathway that controls protein homeostasis, can explain the cognitive and neuronal deficits in a mouse model of DS (see the Perspective by Halliday and Mallucci). These insights into the biological basis underlying DS could potentially help in the design of treatments for this condition. Science , this issue p. 843 ; see also p. 797