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.

The cyclic AMP phenotype of fragile X and autism

“…We have termed this line of thought the cAMP theory of FX (Kelley, Davidson et al 2006;Kelley, Davidson et al 2007) to distinguish it from the mGluR theory (Bear, Huber et al 2004). …”

“…Cyclic AMP production in the FX brain was examined for the first time (Kelley, Davidson et al 2007) by comparing cAMP levels across fly heads, mouse cortex, and human neural cell lines (Bhattacharyya, McMillan et al 2008). Induced cAMP levels are reduced in FX and all three models have deficient stimulated cAMP production.…”

“…In addition, EphB2, a key component in dendritic spine formation with contributions to abnormal pruning in FX (Ethell, Irie et al 2001;Henkemeyer and Frisen 2001;Irie and Yamaguchi 2004), is a likely candidate to influence development of cAMP responsiveness to forskolin (Ibrisimovic, Bilban et al 2007). The mechanism for the distinctive development of the FX cAMP response remains unknown (Kelley, Davidson et al 2007) but the maturation of AC responsiveness in FX is likely related to FMRP loss or its downstream consequences.…”

“…The coupling of the mGluR1 receptor to a given cascade has been localized to the carboxy terminal (Gabellini, Manev et al 1993) and to intracellular loops two and three (Francesconi and Duvoisin 1998). Further studies are necessary to determine whether the cAMP and mGluR mechanisms occur in series or in parallel (Kelley, Davidson et al 2007). …”

Examination of the mGluR-mTOR Pathway for the Identification of Potential Therapeutic Targets to Treat Fragile X

“…1A). Based on the fly data, tissue culture work, the mouse model and samples from humans afflicted with Fragile X syndrome, we speculated that cAMP levels are suppressed (Berry-Kravis and Sklena, 1993;Berry-Kravis et al, 1995;Berry-Kravis and Ciurlionis, 1998;McBride et al, 2005;Kelley et al, 2007). PDE-4 inhibition should increase cAMP signaling by preventing the breakdown of cAMP that is produced during synaptic stimulation.…”