Hippocampal Inhibitory Interneuron-Specific DREADDs Treatment Alters mTORC1-4E-BP Signaling and Impairs Memory...

Control of protein synthesis via the mechanistic target of rapamycin complex 1 (mTORC1) is essential for learning and memory. However, the cell-type-specific and spatiotemporal regulation of this pathway during memory formation is not well understood. In this study, we expressed artificial human muscarinic M3 [hM3D(Gq)] or M4 [hM4D(Gi)] designer receptors exclusively activated by designer drugs (DREADDs) in hippocampal CA1 excitatory or inhibitory neurons of adult mice. We studied the impact of clozapine-N-oxide (CNO), a synthetic DREADDs agonist, on the mTORC1 pathway and long-term memory. hM3D(Gq) and hM4D(Gi) activate or inactivate, respectively, mTORC1 signaling in hippocampal interneurons, as indicated by the phosphorylation of its targets, eukaryotic initiation factor 4E-binding proteins (4E-BP1/2) and ribosomal protein S6 (S6). Activation of either hM3D(Gq) or hM4D(Gi) in mice immediately after training in memory tasks impaired long-term memory formation in inhibitory, but not in excitatory neurons. The findings underscore the importance of activity-dependent mTORC1-4E-BP1/2 signaling in hippocampal inhibitory interneurons for memory formation.