Dietary magnesium supplement enhances memory through Hippo signaling

Dietary magnesium (Mg2+) supplement enhances memory in mammals and Drosophila, but whether and how Mg2+ changes molecular states of neurons, remains unknown. Here we used single-cell RNA sequencing to map cell-type specific transcriptional responses to memory-enhancing dietary Mg2+. These analyses revealed changes in Hippo-pathway gene expression in memory-relevant {beta} Kenyon Cells (KCs) of the mushroom bodies. Targeted knock-down of Merlin, hippo (hpo) and warts demonstrated requirement in {beta} KCs for Mg2+-enhanced, but not baseline memory. Further study of Hippo signaling identified Yorkie (yki) transcriptional coactivator and DNA-binding partner Scalloped (sd) to be required for baseline and Mg2+-enhanced memory. Moreover, releasing Yki::Sd of inhibition from Tondu-domain containing growth inhibitor (Tgi) specifically in {beta} KCs enhanced memory, independent of diet. Analyses of Yki::Sd target genes identified several required in {beta} KCs for baseline memory, including crb and Glut1 which are also Mg2+-induced in a Hippo-dependent manner in {beta} KCs. These genes suggest that aiding the metabolic demands of long-term memory and facilitating structural neuronal plasticity are key mediators of Mg2+-induced memory enhancement. We propose pharmacological enhancement of Sd-dependent transcription, and activity of particular Sd-target genes may have therapeutic potential for memory disorders.