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).
Dr. Manavi Chatterjee, a talented new postdoc in the lab, is now in charge of the FXS project. Dr. Chatterjee has been working on whether inhibiting STEP pharmacologically will have similar outcomes as the genetic reduction of STEP in Fmr1 KO mice and is using the newly discovered STEP inhibitor TC-2153 for these experiments.
We are also testing the hypothesis that STEP regulates the development of dendritic spine morphology. Patient with FXS and Fmr1 KO mice have disrupted spine morphology with many more immature spines (Irwin et. al 2001, Comery et. al 1997). Dr. Chatterjee’s work will determine whether STEP inhibition that reverses cognitive and behavioral deficits can also ameliorate the dendritic morphological deficits present in Fmr1 KO mice.
- Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.Goebel-Goody SM, Wilson-Wallis ED, Royston S, Tagliatela SM, Naegele JR, Lombroso PJ. Genes Brain Behav. 2012 Jul; 2012 Apr 6. PMID: 22405502.
- FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB. Cell. 2011 Jul 22. PMID: 21784246.
- Reversing the effects of fragile X syndrome.Ogren MP, Lombroso PJ. J Am Acad Child Adolesc Psychiatry. 2008 Aug. PMID: 18645420.
- Fragile X syndrome: keys to the molecular genetics of synaptic plasticity.Lombroso PJ, Ogren MP. J Am Acad Child Adolesc Psychiatry. 2008 Jul. PMID: 18574398.
- Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination.Irwin SA, Patel B, Idupulapati M, Harris JB, Crisostomo RA, Larsen BP, Kooy F, Willems PJ, Cras P, Kozlowski PB, Swain RA, Weiler IJ, Greenough WT. Am J Med Genet. 2001 Jan 15. PMID: 11223852.
- Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits.Comery TA, Harris JB, Willems PJ, Oostra BA, Irwin SA, Weiler IJ, Greenough WT. Proc Natl Acad Sci U S A. 1997 May 13. PMID: 9144249.