A rapid and dynamic role for FMRP in the plasticity of adult neurons

Fragile X syndrome (FXS) is a neuro-developmental disorder caused by silencing Fmr1, which encodes the RNA-binding protein FMRP. Although Fmr1 is expressed in adult neurons, it has been challenging to separate acute from chronic effects of loss of Fmr1 in models of FXS. We have used the precision of Drosophila genetics to test if Fmr1 acutely affects adult neuronal plasticity in vivo, focusing on the s-LNv circadian pacemaker neurons that show 24-hour rhythms in structural plasticity. We found that over-expressing Fmr1 for only 4 hours blocks the activity-dependent expansion of s-LNv projections without altering the circadian clock or activity-regulated gene expression. Conversely, reducing Fmr1 expression prevented retraction of s-LNv projections. One FMRP target we identified in s-LNvs is sif, which encodes a Rac1 GEF. Our data indicate that FMRP normally reduces sif mRNA translation at dusk to lower Rac1 activity and acutely regulate neuronal plasticity. To identify the targets of Fmr1 in s-LNvs we expressed ADARcd and Fmr1-ADARcd in the s-LNvs of adult flies. We sorted their LNvs by using the Pdf-RFP transgene and then performed RNA-seq. Genomic DNA was isolated from flies which had the different transgenes to remove the posibility of SNPs being identified as targets.