Enhanced corticosteroid signaling alters synaptic plasticity in the dentate gyrus in mice lacking the fragile X mental retardation protein.
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.
Graduate Program in Neuroscience, University of Victoria, Victoria, BC, Canada; Department of Biology, University of Victoria, Victoria, BC, Canada; Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
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M
Ghilan
Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
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BN
Hryciw
Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
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Brocardo
Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
C A
CA
Bostrom
Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
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Gil-Mohapel
Graduate Program in Neuroscience, University of Victoria, Victoria, BC, Canada; Department of Biology, University of Victoria, Victoria, BC, Canada; Division of Medical Sciences, University of Victoria, Victoria, BC, Canada; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada. Electronic address: brain64@uvic.ca.
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BR
Christie
D000305:Adrenal Cortex Hormones / Q000097:blood*; D000818:Animals; D018891:Dentate Gyrus / Q000378:metabolism*; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D006727:Hormone Antagonists / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015735:Mifepristone / Q000627:therapeutic use; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D018408:Patch-Clamp Techniques; D012149:Restraint, Physical / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013315:Stress, Psychological / Q000188:drug therapy / Q000209:etiology; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D000305:Adrenal Cortex Hormones; D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D006727:Hormone Antagonists; D015735:Mifepristone; D014633:Valine; C497684:Fmr1 protein, mouse; C056639:2-amino-5-phosphopentanoic acid
Dentate gyrus; FMRP; Fmr1; Fragile X; Hippocampus; LTP; NMDA; Stress; Synaptic plasticity