Titrating synapse number to treat MDD in Fragile X Syndrome

Rapid antidepressants are novel treatments for major depressive disorder (MDD) and work by blocking N-methyl-aspartate receptors (NMDAR), which, in turn, activate the protein synthesis pathway regulated by mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Our recent work demonstrates that the RNA-binding protein Fragile X Mental Retardation Protein (FMRP) is downregulated in dendrites upon treatment with a rapid antidepressant. Here, we show that the behavioral effects of the rapid antidepressant Ro-25-6981 requires FMRP expression and promotes differential mRNA binding to FMRP in an mTORC1-dependent manner. Further, these mRNAs are identified to regulate transsynaptic signaling. Using a novel technique, we show that synapse formation underlying the behavioral effects of Ro-25-6981 require GABABR-mediated mTORC1 activity in WT animals. Finally, we demonstrate that in a clinically relevant animal model of Fragile X Syndrome (FXS), which lacks FMRP expression, GABABR activity is detrimental to the effects of Ro-25-6981. These effects are rescued when GABABRs are blocked in addition to treatment with Ro-25-6981, indicating that rapid antidepressants alone may not be an effective treatment for people with FXS and MDD.