Role of FMRP in rapid antidepressant effects and synapse regulation

Abstract

Rapid antidepressants are novel treatments for major depressive disorder (MDD) and work by blocking N-methyl-D-aspartate receptors (NMDARs), 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 require FMRP expression, and treatment 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 requires GABABR-mediated mTORC1 activity in WT animals. Finally, we demonstrate that in an animal model that lacks FMRP expression and has clinical relevance for Fragile X Syndrome (FXS), GABABR activity is detrimental to the effects of Ro-25-6981. These effects are rescued with the combined therapy of blocking GABABRs and NMDARs, indicating that rapid antidepressants alone may not be an effective treatment for people with comorbid FXS and MDD.

A paradoxical switch: the implications of excitatory GABAergic signaling in neurological disorders

“…As noted, the antidepressive properties of both ethanol and rapid antidepressants share similar molecular mechanisms in which GABA B Rs are uncoupled from GIRK channels to L-type voltage-gated calcium channels, resulting in depolarization. Ethanol and rapid antidepressants, moreover, require FMRP to switch GABA B Rs from inhibitory to excitatory ( 166 , 183 ). Following exposure to ethanol, FMRP levels are additionally reduced in neuronal dendrites ( 166 ).…”

“…It could therefore be hypothesized that ethanol-induced downregulation of FMRP could subsequently increase NKCC1 to cause a disturbance in chloride homeostasis, exacerbating the reinforcing properties for ethanol. Previous work ( 183 ) presents a novel therapeutic strategy to alleviate synapse loss in a model where FMRP is absent. A combination of both Ro-25-6981 (Ro), a GluN2B-specific antagonist, and CGP35348 (CGP), a GABA B R receptor antagonist, increased synapse number and rescued depressive-like symptoms in Fmr1 KO mice ( Figure 7 ).…”

p85S6K sustains synaptic GluA1 to ameliorate cognitive deficits in Alzheimer’s disease

“…SYNPLA was used to detect synaptic insertion of GluA1-containing AMPA receptors as previously described with mild modifications [ 26 , 27 ]. Dore et al used presynaptic binding protein neurexin 1b and GluA1 to detect the synaptic insertion of GluA1 [ 26 ].…”

“…Dore et al used presynaptic binding protein neurexin 1b and GluA1 to detect the synaptic insertion of GluA1 [ 26 ]. Heaney et al used a similar PLA assay with presynaptic protein synapsin-1 and postsynaptic PSD95 to detect synaptic changes [ 27 ]. Here, we used the presynaptic protein synaptophysin to detect synaptic insertion of GluA1.…”

A decrease in NR2B expression mediated by DNA hypermethylation induces perioperative neurocognitive disorder in aged mice

“…An equal volume of saline was used as a control. For the NR2B intervention experiment, ifenprodil (Sigma–Aldrich) or RO25‐6981 (Med Chem Express) was dissolved in saline and intraperitoneally administered at a dose of 10 mg/kg three times at 48‐hour intervals starting immediately after the laparotomy 25,26 …”