ATF4 Modulates Group 1 mGluR-Dependent molecular signaling, hippocampal plasticity and behavior

Group 1 metabotropic glutamate receptors (Gp1 mGluRs) are critical effectors in behavior. Abnormal Gp1 mGluR signaling is frequently observed in neurodevelopmental and cognitive disorders. It is established that activation of Gp1 mGluR elicits translation-dependent neuronal plasticity mechanisms, such as long-term synaptic depression (LTD). However, whether and how transcription is involved is not clear. In this study, we study a cellular stress associated transcription factor, activation transcription factor 4 (ATF4). We first employed RNA sequencing and revealed that knocking down ATF4 using ATF4 heterozygous mice upregulates or downregulates multiple genes with known functions in translational control or synaptic plasticity in a sex-dependent manner. When searching for a crosstalk between ATF4 and known synaptic plasticity mechanisms, we found that activation of Gp1 mGluR promotes the expression and nuclear distribution of ATF4. Using ATF4 heterozygous mice, we further confirmed that ATF4 is required for Gp1 mGluR-induced activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), de novo translation and hippocampal LTD at Schaffer-collateral synapses. When assessing animal behavior, our results indicated that knocking down ATF4 impairs learning behavior and precludes mGluR-dependent reduction in repetitive behavior only in female mice. Altogether, our study suggests ATF4 as an activity-dependent transcription factor required for Gp1 mGluR-dependent translation, hippocampal LTD, and behavior.