Reversal of activity-mediated spine dynamics and learning impairment in a mouse model of Fragile X syndrome.
Fragile X syndrome (FXS) is characterized by intellectual disability and autistic traits, and results from the silencing of the FMR1 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 (PI3K) 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 PI3K signaling could contribute to improve the cognitive deficits associated with FXS.
Department of Basic Neurosciences, School of Medicine, University of Geneva, Geneva 4 1211, Switzerland.
Bernadett
B
Boda
Pablo
P
Mendez
Benjamin
B
Boury-Jamot
Fulvio
F
Magara
Dominique
D
Muller
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D003071:Cognition; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000235:genetics / Q000503:physiopathology*; D017774:Long-Term Potentiation; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors
D051860:Fragile X Messenger Ribonucleoprotein 1; D019869:Phosphatidylinositol 3-Kinases; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse
LTD; LTP; memory; spinogenesis; synaptic plasticity; water maze