UC Santa Cruz

The Fragile X Syndrome (FXS), the most common inherited intellectualdisability, is caused by a loss-of-function mutation in the FMR1 gene encoding the Fragile X Messenger Ribonucleoprotein (FMRP). The morphological hallmark of FXS in humans and Fmr1 knockout (KO) mice is an abnormally high density and immature morphology of dendritic spines on cortical pyramidal neurons (PyrNs). To determine whether this phenotype arises cell-autonomously from the lack of FMRP, we sparsely deleted FMRP from layer 5 PyrNs and imaged these cells in vivo in adolescence and adulthood. We found that single-cell Fmr1 KO in adulthood does not affect spine density, morphology, or dynamics, but neonatal Fmr1 KO leads to normal spine density yet elevated spine formation at 1 month of age. These data reveal cell-autonomous FMRP regulation of cortical synaptic dynamics during adolescence, but spine defects in adulthood also implicate non-cell-autonomous factors.