Role of FMRP in rapid antidepressant effects and synapse regulation.

Autor: Heaney CF; Department of Physiology and Pharmacology, Wake Forest University Health Sciences, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA.; Wake Forest Translational Alcohol Research Center (WF-TARC), Wake Forest University Health Sciences, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA., Namjoshi SV; Department of Physiology and Pharmacology, Wake Forest University Health Sciences, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA., Uneri A; Department of Physiology and Pharmacology, Wake Forest University Health Sciences, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA., Bach EC; Department of Physiology and Pharmacology, Wake Forest University Health Sciences, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA.; Wake Forest Translational Alcohol Research Center (WF-TARC), Wake Forest University Health Sciences, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA., Weiner JL; Department of Physiology and Pharmacology, Wake Forest University Health Sciences, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA.; Wake Forest Translational Alcohol Research Center (WF-TARC), Wake Forest University Health Sciences, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA., Raab-Graham KF; Department of Physiology and Pharmacology, Wake Forest University Health Sciences, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA. kraabgra@wakehealth.edu.; Wake Forest Translational Alcohol Research Center (WF-TARC), Wake Forest University Health Sciences, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA. kraabgra@wakehealth.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2021 Jun; Vol. 26 (6), pp. 2350-2362. Date of Electronic Publication: 2021 Jan 12.
DOI: 10.1038/s41380-020-00977-z
Abstrakt: 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 GABA B R-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), GABA B R activity is detrimental to the effects of Ro-25-6981. These effects are rescued with the combined therapy of blocking GABA B Rs and NMDARs, indicating that rapid antidepressants alone may not be an effective treatment for people with comorbid FXS and MDD.
(© 2021. The Author(s).)
Databáze: MEDLINE
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