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Significance Fragile X syndrome (FXS) is a frequent mental disorder characterized by intellectual disability and other symptoms including autism. The disease gene-encoded protein FMRP regulates activity-dependent translation of a large number of mRNAs in neurons. We used quantitative mass spectrometry to systematically compare protein expression in neocortical synaptic fractions betweenFmr1 (fragile X mental retardation 1) knockout (KO) and wild-type mice during adolescence and adulthood. We discovered an upregulation of a large number of synaptic proteins in young KO mice but not in adult ones. Many of the upregulated proteins are correlated with an increased protein synthesis in KO neurons. This study provides a greatly expanded view of protein-level changes in FXS and identifies a previously unrecognized developmental dynamics in FXS pathogenesis.

Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome