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

M Ghilan; B N Hryciw; P S Brocardo; C A Bostrom; J Gil-Mohapel; B R Christie

doi:10.1016/j.nbd.2015.01.008

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.

Authors

M Ghilan¹, B N Hryciw², P S Brocardo², C A Bostrom², J Gil-Mohapel², B R Christie³

Affiliations

¹ 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.
² Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
³ 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.

PMID: 25731748
DOI: 10.1016/j.nbd.2015.01.008

Abstract

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

Substances

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

Grants and funding

Canadian Institutes of Health Research/Canada