ATF4, a stress-response transcription factor, directly regulates metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD), a critical synaptic plasticity mechanism that weakens neural connections. This finding establishes ATF4 as a key molecular bridge between cellular stress responses and synaptic function, revealing how the integrated stress response pathway influences learning and memory formation at the cellular level. The research demonstrates that ATF4 controls specific behavioral outcomes tied to synaptic depression, suggesting this protein serves dual roles in both metabolic stress management and neural adaptation. This connection between stress signaling and synaptic plasticity offers fresh insight into neurodegenerative diseases where both systems are disrupted. Alzheimer's, autism spectrum disorders, and fragile X syndrome all feature aberrant mGluR-LTD, making ATF4 a potential therapeutic target. The finding is particularly significant because ATF4 is already known to regulate protein synthesis during stress, and this research extends its influence into fundamental brain plasticity mechanisms. However, the work appears to be primarily mechanistic, conducted in laboratory models, so clinical relevance remains to be established. Still, identifying ATF4's dual role in metabolism and cognition could reshape approaches to treating neurological conditions where synaptic dysfunction intersects with cellular stress.