Fragile X Syndrome

Fragile X syndrome is a developmental disorder that is one of the translational neuroscience projects in the lab. FXS is due to transcriptional silencing of Fmr1 gene that encodes Fragile X mental retardation protein (FMRP). FMRP acts as a translation repressor to some synaptic proteins, while mutation of Fmr1 gene can lead to increased translation of these proteins.

STEP is over-expressed in a mouse model of FXS (Fmr1 KO mice). Similar to what we were finding in other disorders with increased STEP expression, we hypothesized that the increase in STEP expression might disrupt synaptic strengthening and contribute to the cognitive and behavioral deficits present in FXS. Dr. Susan Goebel-Goody (currently Senior Principal Scientist, Pfizer) tested this hypothesis. She first established that FMRP bound to STEP mRNA (Goebel-Goody et al., 2012), confirming that FMRP might regulate STEP translation (Darnell et al., 2011). She then established that genetic reduction of STEP led to amelioration of key behavioral abnormalities found in this disorder. She carried out an extensive characterization of the effects of STEP reduction in Fmr1 KO mice in audiogenic seizures and various models of social (social dominance tube task, 3-chambered social task) and non-social anxiety (light dark, elevated plus maze, open field task). Usually Fmr1 KO mice are socially anxious and when they are in the same plastic tube (head to head) as the WT mice, they typically back out of the tube. Genetic reduction of STEP led to an increase in the percentage wins for Fmr1 KO mice (Fig 2).