Nicole Calakos

The integrated stress response (ISR) is a highly conserved biochemical pathway that regulates protein synthesis. The ISR is activated in response to diverse stressors to restore cellular homeostasis. As such, the ISR is implicated in a wide range of diseases, including brain disorders. However, in the brain, the ISR also has potent influence on processes beyond proteostasis, namely synaptic plasticity, learning and memory. Thus, in the setting of brain diseases, ISR activity may have dual effects on proteostasis and synaptic function. In this review, we consider the ISR's contribution to brain disorders through the lens of its potential effects on synaptic plasticity. From these examples, we illustrate that at times ISR activity may be a “double-edged sword”. We also highlight its potential as a therapeutic target to improve circuit function in brain diseases independent of its role in disease pathogenesis.

The integrated stress response (ISR) is a core pathway for maintaining cellular proteostasis and a key regulator of translation in processes beyond the cellular response to stress. For example, the ISR regulates developmental axonogenesis, learning and memory, and synaptic plasticity in the brain. One barrier to uncovering ISR roles in health and disease is the challenge of monitoring its activity. The transient nature of regulatory phosphorylation events and lack of transgenic ISR reporter mouse lines make visually capturing the molecular hallmarks of ISR activation in specific cell types especially difficult. We recently developed the SPOTlight (Selective Phospho-eIF2alpha Open reading frame Tracking light) reporter, which uniquely provides a readout of the functional state of protein synthesis initiation dynamics that are regulated by the ISR. Here, we report the generation of a transgenic mouse line with Cre-dependent expression of SPOTlight. This resource enables selective visualization of ISR-regulated functional activity across genetically defined cell populations body-wide. Using a pan-neuronal Cre line (Nestin-Cre), we demonstrate the reporter's performance and applications for cell-specific discovery, live tissue assessments and quantitative comparisons across broad physical space. We also specifically investigated the extent to which the property of steady-state basal ISR activation, recently described in dorsal striatal cholinergic interneurons, extends to other classes of cholinergic neurons and provide a CNS-wide atlas of SPOTlight activity in these cells. The DIO-SPOTlight mouse enables a wide range of studies in all organ systems and functional monitoring opportunities not previously accessible.