title: The cyclic AMP cascade is altered in the fragile X nervous system.
abstract: Fragile X syndrome (FX), the most common heritable cause of mental retardation and autism, is a developmental disorder characterized by physical, cognitive, and behavioral deficits. FX results from a trinucleotide expansion mutation in the fmr1 gene that reduces levels of fragile X mental retardation protein (FMRP). Although research efforts have focused on FMRP's impact on mGluR signaling, how the loss of FMRP leads to the individual symptoms of FX is not known. Previous studies on human FX blood cells revealed alterations in the cyclic adenosine 3', 5'-monophosphate (cAMP) cascade. We tested the hypothesis that cAMP signaling is altered in the FX nervous system using three different model systems. Induced levels of cAMP in platelets and in brains of fmr1 knockout mice are substantially reduced. Cyclic AMP induction is also significantly reduced in human FX neural cells. Furthermore, cAMP production is decreased in the heads of FX Drosophila and this defect can be rescued by reintroduction of the dfmr gene. Our results indicate that a robust defect in cAMP production in FX is conserved across species and suggest that cAMP metabolism may serve as a useful biomarker in the human disease population. Reduced cAMP induction has implications for the underlying causes of FX and autism spectrum disorders. Pharmacological agents known to modulate the cAMP cascade may be therapeutic in FX patients and can be tested in these models, thus supplementing current efforts centered on mGluR signaling.
authors: Waisman Laboratory for Brain Imaging and Behavior, Waisman Center, University of Wisconsin, Madison, Wisconsin, USA.
authors: Daniel J
authors: DJ
authors: Kelley
authors: Richard J
authors: RJ
authors: Davidson
authors: Jamie L
authors: JL
authors: Elliott
authors: Garet P
authors: GP
authors: Lahvis
authors: Jerry C P
authors: JC
authors: Yin
authors: Anita
authors: A
authors: Bhattacharyya
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004330:Drosophila; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009420:Nervous System / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism
chemical_list: D000242:Cyclic AMP; D051860:Fragile X Messenger Ribonucleoprotein 1