Enhanced corticosteroid signaling alters synaptic plasticity in the dentate gyrus in mice lacking the fragile X mental retardation protein

Neurobiol Dis. 2015 May;77:26-34. doi: 10.1016/j.nbd.2015.01.008. Epub 2015 Feb 27.


The fragile X mental retardation protein (FMRP) is an important regulator of protein translation, and a lack of FMRP expression leads to a cognitive disorder known as fragile X syndrome (FXS). Clinical symptoms characterizing FXS include learning impairments and heightened anxiety in response to stressful situations. Here, we report that, in response to acute stress, mice lacking FMRP show a faster elevation of corticosterone and a more immediate impairment in N-methyl-d-aspartate receptor (NMDAR) dependent long-term potentiation (LTP) in the dentate gyrus (DG). These stress-induced LTP impairments were rescued by administering the glucocorticoid receptor (GR) antagonist RU38486. Administration of RU38486 also enhanced LTP in Fmr1(-/y) mice in the absence of acute stress to wild-type levels, and this enhancement was blocked by application of the NMDAR antagonist 2-amino-5-phosphonopentanoic acid. These results suggest that a loss of FMPR results in enhanced GR signaling that may adversely affect NMDAR dependent synaptic plasticity in the DG.

Keywords: Dentate gyrus; FMRP; Fmr1; Fragile X; Hippocampus; LTP; NMDA; Stress; Synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / blood*
  • Animals
  • Dentate Gyrus / metabolism*
  • Electric Stimulation
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism*
  • Hormone Antagonists / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mifepristone / therapeutic use
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics*
  • Patch-Clamp Techniques
  • Restraint, Physical / adverse effects
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Stress, Psychological / drug therapy
  • Stress, Psychological / etiology
  • Time Factors
  • Valine / analogs & derivatives
  • Valine / pharmacology


  • Adrenal Cortex Hormones
  • Excitatory Amino Acid Antagonists
  • Fmr1 protein, mouse
  • Hormone Antagonists
  • Fragile X Mental Retardation Protein
  • Mifepristone
  • 2-amino-5-phosphopentanoic acid
  • Valine