The ISR downstream effector ATF4 promotes mGluR-dependent long-term depression and associated behavior

The integrated stress response (ISR) plays a crucial role in cognition via bidirectional modulation of the two major forms of synaptic plasticity, long-term potentiation, and long-term depression (LTD). Specifically, inhibition of the ISR blocks metabotropic glutamate receptor-dependent LTD (mGluR-LTD), whereas its activation facilitates this form of synaptic depression. However, the contribution of activating transcription factor 4 (ATF4), the best studied downstream effector of the ISR, to mGluR-LTD remains unknown. Here, we show that pharmacological activation of group I mGluRs in mouse hippocampal slices increases ATF4 protein levels without altering its transcription and concurrently downregulates the expression of oxidative phosphorylation (OXPHOS) proteins. Selective deletion of ATF4 in excitatory neurons impairs mGluR-LTD and prevents the downregulation of OXPHOS proteins. Notably, administration of a small molecule inhibitor of OXPHOS rescues the impaired mGluR-LTD in ATF4-depleted hippocampal slices, indicating that ATF4 regulates this type of synaptic plasticity by modulating mitochondrial function. Moreover, ATF4 deletion in excitatory neurons disrupts object-place learning, an mGluR-LTD-dependent behavior paradigm. Together, these findings reveal a role of ATF4 as a key mediator of protein synthesis-regulated synaptic depression and related behaviors.