Fig. 1.

Biological roles of synaptic FMRP and CYFIP1 in postsynaptic neurons. FMRP plays a key role in negatively regulating the translation of hundreds of FMRP targets, including activity-regulated cytoskeleton associated (ARC), by forming a complex with CYFIP1, alongside the initiation factor eIF4e. The control of mRNA translation, and its repression by the CYFIP1-FMRP complex, is partly mediated through activation of upstream NMDA and mGluR5 receptors. FMRP targets such as ARC can drive changes in synaptic plasticity through regulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking/internalization and increasing actin cytoskeleton stability. Meanwhile, CYFIP1 can bind and inhibit the WAVE regulatory complex, thereby blocking the promotion of actin cytoskeleton rearrangements. Preclinical evidence suggests that under conditions of synaptic activation, CYFIP1 redistributes between the 2 main complexes, with greater association with the WAVE complex and a reciprocal decrease with the FMRP complex. FMRP, fragile-X mental retardation protein; CYFIP1, cytoplasmic FMRP-interacting protein; mGluR5, metabotropic glutamate receptor 5.