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Reversal of activity‐mediated spine dynamics and learning impairment in a mouse model of F ragile X syndrome
Author(s) -
Boda Bernadett,
Mendez Pablo,
BouryJamot Benjamin,
Magara Fulvio,
Muller Dominique
Publication year - 2014
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.12488
Subject(s) - fmr1 , metabotropic glutamate receptor , fragile x syndrome , dendritic spine , neuroscience , synaptic plasticity , long term potentiation , biology , glutamate receptor , synapse , microbiology and biotechnology , hippocampal formation , receptor , biochemistry , genetics , fragile x , gene
Fragile X syndrome ( FXS ) is characterized by intellectual disability and autistic traits, and results from the silencing of the FMR 1 gene coding for a protein implicated in the regulation of protein synthesis at synapses. The lack of functional Fragile X mental retardation protein has been proposed to result in an excessive signaling of synaptic metabotropic glutamate receptors, leading to alterations of synapse maturation and plasticity. It remains, however, unclear how mechanisms of activity‐dependent spine dynamics are affected in Fmr knockout ( Fmr1 ‐ KO ) mice and whether they can be reversed. Here we used a repetitive imaging approach in hippocampal slice cultures to investigate properties of structural plasticity and their modulation by signaling pathways. We found that basal spine turnover was significantly reduced in Fmr1 ‐ KO mice, but markedly enhanced by activity. Additionally, activity‐mediated spine stabilization was lost in Fmr1 ‐ KO mice. Application of the metabotropic glutamate receptor antagonist α‐Methyl‐4‐carboxyphenylglycine (MCPG) enhanced basal turnover, improved spine stability, but failed to reinstate activity‐mediated spine stabilization. In contrast, enhancing phosphoinositide‐3 kinase ( PI 3 K ) signaling, a pathway implicated in various aspects of synaptic plasticity, reversed both basal turnover and activity‐mediated spine stabilization. It also restored defective long‐term potentiation mechanisms in slices and improved reversal learning in Fmr1 ‐ KO mice. These results suggest that modulation of PI 3K signaling could contribute to improve the cognitive deficits associated with FXS .