Excess PI3K subunit synthesis and activity as a novel therapeutic target in Fragile X Syndrome

• Type of Material: Article
• Authors: Christina Gross, Emory University; Mika Nakamoto, Emory University; Xiaodi Yao, Emory University; Chi Bun Chan, Emory University; So Y. Yim, Emory University; Keqiang Ye, Emory University; Stephen Warren, Emory University; Gary Bassell, Emory University
• Language: English
• Date: 2010-08-11
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 the authors
• Final Published Version (URL): http://www.jneurosci.org/content/30/32/10624
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0888-0395
• Volume: 30
• Issue: 32
• Start Page: 10624
• End Page: 10638
• Grant/Funding Information: This work was supported by a postdoctoral fellowship from NFXF to C.G., NIH MH085617 to G.J.B., NIH HD020521 to S.T.W. and the Fragile X Center, 3P30HD024064 to S.T.W. and G.J.B.; National Institute of Child Health & Human Development : NICHD; National Institute on Drug Abuse : NIDA; National Institute of Mental Health : NIMH
• Keywords: protein synthesis; FMRP; AMPAR; phosphatidylinositol-3-kinase; mGluR theory of FXS; dendritic spine
• Research Categories: Biology, Neuroscience; Biology, Cell; Health Sciences, Pathology

Abstract

Fragile X Syndrome (FXS) is an inherited neurologic disease caused by loss of Fragile X Mental Retardation Protein (FMRP), which is hypothesized to mediate negative regulation of mRNA translation at synapses. A prominent feature of FXS animal models is exaggerated signaling through group 1 metabotropic glutamate receptors (gp1 mGluRs), and therapeutic strategies to treat FXS are targeted mainly at gp1 mGluRs. Recent studies, however, indicate that a variety of receptor-mediated signal transduction pathways are dysregulated in FXS, suggesting that FMRP acts on a common downstream signaling molecule. Here, we show that deficiency of FMRP results in excess synaptic activity of phosphoinositide 3-kinase (PI3K), a downstream signaling molecule of many cell surface receptors. In Fmr1 knockout neurons, excess PI3K activity can be reduced by perturbation of gp1 mGluR-mediated signaling. Remarkably, increased PI3K activity was also observed in non-neuronal cells in the absence of gp1 mGluRs. Here, we show that FMRP regulates the synthesis and synaptic localization of p110β, the catalytic subunit of PI3K. In wild type, gp1 mGluR activation induces p110β translation, p110β protein expression and PI3K activity. In contrast, both p110β protein synthesis and PI3K activity are elevated and insensitive to gp1 mGluR stimulation in Fmr1 knockout. This suggests that dysregulated PI3K signaling may underlie the synaptic impairments in FXS. In support of this hypothesis, we show that PI3K antagonists rescue three FXS-associated phenotypes: dysregulated synaptic protein synthesis, excess AMPA receptor internalization and increased spine density. Targeting excessive PI3K activity might thus be a potent therapeutic strategy for FXS.