Fragile X-like behaviors and abnormal cortical dendritic spines in Cytoplasmic FMR1-interacting protein 2-mutant mice

Silencing of fragile X mental retardation 1 (FMR1) gene and loss of fragile X mental retardation protein (FMRP) cause fragile X syndrome (FXS), a genetic disorder characterized by intellectual disability and autistic behaviors. FMRP is an mRNA-binding protein regulating neuronal translation of target mRNAs. Abnormalities in actin-rich dendritic spines are major neuronal features in FXS, but the molecular mechanism and identity of FMRP targets mediating this phenotype remain largely unknown. Cytoplasmic FMR1-interacting protein 2 (Cyfip2) was identified as an interactor of FMRP, and its mRNA is a highly ranked FMRP target in mouse brain. Importantly, Cyfip2 is a component of WAVE regulatory complex, a key regulator of actin cytoskeleton, suggesting that Cyfip2 could be implicated in the dendritic spine phenotype of FXS. Here,we generated and characterized Cyfip2- mutant (Cyfip2^+/-) mice.We found that Cyfip2^+/- mice exhibited behavioral phenotypes similar to Fmr1-null (Fmr1^-/y) mice, an animal model of FXS. Synaptic plasticity and dendritic spineswere normal in Cyfip2^+/- hippocampus. However, dendritic spines were altered in Cyfip2^+/- cortex, and the dendritic spine phenotype of Fmr1^-/y cortexwas aggravated in Fmr1^-/y; Cyfip2^+/- doublemutant mice. In addition to the spine changes at basal state, metabotropic glutamate receptor (mGluR)-induced dendritic spine regulation was impaired in both Fmr1^-/y and Cyfip2^+/- cortical neurons. Mechanistically, mGluR activation induced mRNA translation-dependent increase of Cyfip2 in wild-type cortical neurons, but not in Fmr1^-/y or Cyfip2^+/- neurons. These results suggest that misregulation of Cyfip2 function and its mGluR-induced expression contribute to the neurobehavioral phenotypes of FXS.